Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans

Bioorganic & Medicinal Chemistry 23 (2015) 532–547

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: w ww.elsevier.com/locate/bmc

Design, synthesis, and biological evaluation of aminothiazole

derivatives against the fungal pathogens Histoplasma

capsulatum and Cryptococcus neoformans

Ahmed Khalil ^a,b, Jessica A. Edwards ^c,d,e, Chad A. Rappleye ^c,d,e, Werner Tjarks ^a,e,

⇑

^aDivision of Medicinal Chemistry & Pharmacognosy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA

^bChemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt

^cDepartment of Microbiology, The Ohio State University, USA

^dDepartment of Microbial Infection and Immunity, The Ohio State University, USA

^eThe Center for Microbial Interface Biology, The Ohio State University, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

Invasive fungal disease constitutes a growing health burden and development of novel antifungal drugs

with high potency and selectivity against new fungal molecular targets are urgently needed. Previously,

an aminothiazole derivative, designated as 41F5, was identiﬁed in our laboratories as highly active

Received 29 October 2014

Revised 25 November 2014

Accepted 3 December 2014

Available online 10 December 2014

against Histoplasma yeast (MIC₅₀0.4–0.8 lM) through phenotypic high-throughput screening of a com-

mercial library of 3600 purine mimicking compounds (Antimicrob. Agents Chemother. 2013, 57, 4349).

Consequently, 68 analogues of 41F5 were designed and synthesized or obtained from commercial sources

and their MIC₅₀s of growth inhibition were evaluated in Histoplasma capsulatum to establish a basic struc-

ture–activity-relationship (SAR) for this potentially new class of antifungals. The growth inhibiting

potentials of smaller subsets of this library were also evaluated in Cryptococcus neoformans and human

hepatocyte HepG2 cells, the latter to obtain selectivity indices (SIs). The results indicate that a thiazole

core structure with a naphth-1-ylmethyl group at the 5-position and cyclohexylamide-, cyclohexylmeth-

ylamide-, or cyclohexylethylamide substituents at the 2-position caused the highest growth inhibition of

Keywords:

Aminothiazoles

Antifungal activity

Structure–activity-relationship

Histoplasma capsulatum

Cryptococcus neoformans

Histoplasma yeast with MIC₅₀s of 0.4 lM. For these analogues, SIs of 92 to >100 indicated generally low

host toxicity. Substitution at the 3- and 4-position decreased antifungal activity. Similarities and differ-

ences were observed between Histoplasma and Cryptococcus SARs. For Cryptococcus, the naphth-1-

ylmethyl substituent at the 5-position and smaller cyclopentylamide- or cyclohexylamide groups at

the 2-position were important for activity. In contrast, slightly larger cyclohexylmethyl- and cyclohexyl-

ethyl substituents markedly decreased activity.

1. Introduction

fungal infections cause more human deaths than tuberculosis,

although the latter has gained more notoriety in the public

Over the past few decades, systemic and invasive fungal infec-

tions have emerged as a signiﬁcant threat to public health. Invasive

eye.^1,2Cryptococcus infections have been estimated to cause over

500,000 deaths annually among immunocompromised individu-

als.²Invasive fungal infections are not limited to individuals with

compromised immune functions. For example, in the United States,

infections with Cryptococcus gattii and Histoplasma capsulatum

occur in immunocompetent as well as immunocompromised

hosts, classifying these as primary, not just opportunistic, fungal

pathogens.³

The shared eukaryotic nature of both the host and pathogen sig-

niﬁcantly complicates treatment options for fungal disease. Exist-

ing antifungals for systemic mycoses target either the fungal

membrane sterol ergosterol or cell wall b-glucan.⁴Amphotericin

B targets sterols directly and triazole-class antifungals impair

Abbreviations: ATCC, American type culture collection; DMAP, 4-dimethylami-

nopyridine; DMC, dichloromethane; DMF, dimethylformamide; DMSO, dimethyl

sulfoxide; EDAC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; FIC, fractional

inhibitory concentration; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic

acid; HMM, Histoplasma-macrophage media; HR-ESI, high resolution-electrospray

ionization; MEM, minimum essential medium; MIC₅₀, minimal concentration that

inhibits 50% of fungal growth; MIC, minimal inhibitory concentration; MW,

molecular weight; PBS, phosphate-buffered saline; TEA, triethylamine; TFA, triﬂu-

oroacedic acid; TFAA, triﬂuoroacedic anhydride, THF, tetrahydrofuran; SI, selectivity

index; SAR, structure–activity-relationship; YPD, yeast extract peptone dextrose.

⇑

Corresponding author. Tel.: +1 614 292 7624; fax: +1 614 292 2435.

E-mail address: tjarks.1@osu.edu (W. Tjarks).

http://dx.doi.org/10.1016/j.bmc.2014.12.006

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

533

fold.⁷Inhibition of Histoplasma yeast growth was used as the

screening phenotype. Concurrently, we measured mammalian

cytotoxicity using a P388D1 macrophage cell line⁸since macro-

phages are the primary host cell for Histoplasma yeast. Among

the 10 hits with the highest selectivity indices (SIs), a subgroup

of three structurally related thiazole/thiophene derivatives (41F5,

2F8, 4H2, Fig. 1) were identiﬁed. The most active compound of this

group was the aminothiazole 41F5, which had the lowest MIC₅₀

(0.4–0.8 lM) and the highest SI (63–135) of all tested compounds

relative to P388D1 macrophages. Preliminary studies also indi-

cated selective toxicity of 41F5 against Cryptococcus neoformans.⁷

Thus, the aminothiazole 41F5 has efﬁcacy against Histoplasma cap-

sulatum and Cryptococcus neoformans, two fungal pathogens that

have natural resistance against the echinocandin class of

antifungals.

Compounds with aminothiazole scaffold display a wide range of

biological activities,⁹including antiparasitic-,¹⁰antifungal-,¹¹anti-

bacterial-,¹²antitubucular-,¹³antiviral-,¹⁴anticancer-,^15,16and

antiprion¹⁷action. The study described here was carried out to

establish the basic anti-Histoplasma and anti-Cryptococcus speciﬁc

aminothiazole structure–activity relationships (SARs).

Figure 1. Structurally related thiazole/thiophene hit compounds 41F5, 2F8, and

4H2 identiﬁed in a phenotypic high-throughput screen of a purinome-focused

library.⁷

2. Results

2.1. Chemistry

sterol synthesis. However, both antifungal classes have signiﬁcant

host toxicity, which prohibits general prophylactic use of these

antifungals.⁵The echinocandins are a third class of fungistatic anti-

fungals recently developed, which target the synthesis of the

essential fungal cell wall polysaccharide b-glucan. While better tol-

erated than amphotericin and the triazoles, the echinocandins lack

efﬁcacy against the more virulent fungal pathogens Cryptococcus

and Histoplasma.⁶Further complicating antifungal treatment is

the fact that Cryptococcus and Histoplasma yeasts invade immune

cells (e.g., macrophages), and this intracellular location presents

additional barriers to drug accessibility and efﬁcacy. Thus, devel-

opment of antifungal drugs with high potency and selectivity

against new cellular targets are urgently needed to combat the

growing health burden of invasive fungal disease.

The primary objective of our studies was to establish a Histo-

plasma SAR for aminothiazoles based on the 41F5 structure

(Fig. 1). Other objectives were the development of a very basic

Cryptococcus SAR for comparison and the evaluation of toxicity of

promising novel compounds to hepatocyte (HepG2) cells. For this

purpose we synthesized or purchased 68 compounds that are

structurally related to 41F5. The thiazole core structure is easily

amenable to modiﬁcation. Due to its abundant use in drug design,

numerous synthetic approaches have been developed and many

synthetic precursor molecules for thiazole synthesis are commer-

cially available or easily prepared.^15,16,18,19Indeed, the design of

this initial library was based to a signiﬁcant extent on the synthetic

feasibility and/or commercial availability of starting materials.

Established synthetic procedures are shown in Scheme 1.

Recently, our group performed a phenotypic high-throughput

screen of a purinome-focused library of 3600 compounds with

structural similarity to purines or any known purine analogue scaf-

The reaction of compounds 1a and 1b with various aldehydes in

presence of n-Buli at À78 °C afforded compounds 2a–2l in yields

Scheme 1. Reagents and conditions: (a) R₅CHO, n-BuLi, THF, À78 °C, 2 h; (b) Et₃SiH, TFA, DCM, overnight, rt; (c) R₂COCl, Et₃N, THF, 15 min, rt or (d) R₂COOH, EDAC, DMAP,

Et₃N, DMF/DCM (3:1, v/v), 2 h, rt or (e) TFAA, DCM, 30 min, rt. ^aNot applicable.

534

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

ranging from 22% to 59% (Scheme 1). The secondary alcohol

functions of compounds 2a–2l were reduced with triethylsilane

(Et₃SiH) followed by in situ deprotection of the Boc group with tri-

ﬂuoroacetic acid (TFA) in DCM to give compounds 3a–3l in yields

ranging from 53% to 91%. It seems that this synthetic method has

not been described previously for compounds 3a–3l. Acylation of

compounds 3a–3p with various alkyl-, alicyclic-, or aryl acyl chlo-

rides in the presence of triethylamine (TEA) gave products 4b–4f,

4h, 4i, 5h, 6a–6c, 7a–7c, 8a, 8b, 9b–9h, 10a–10f, 11a, 11b,

12a–12d, 13a–13f, 14a, 14c, and 15a–15h.

The reaction of 3a or 3b with triﬂuoroacetic anhydride (TFAA) at

0 °C followed by stirring for 30 min at room temperature yielded

4a and 9a in 56% and 93%, respectively. The reactions of compound

3a with various alicyclic carboxylic acid in presence of 1-ethyl-3-

(3-dimethylaminopropyl) carbodiimide (EDAC) and dimethylami-

nopyridine (DMAP) gave compounds 4g, 5a–5c, and 5g in yields

ranging from 20% to 77%. Carboxylic acids instead of alicyclic acyl

chlorides were used for the synthesis of 4g, 5a–5c, and 5g because

of their commercial availability.

shown in Scheme 1, this reaction led to compounds that were

mono substituted at the amino group at the 2-position (5d–5f) in

low yields (5–8%) and compounds that were disubstituted both

at the amino group in the 2-position and at the N3-position of thi-

azole ring (16b–16d) in yields ranging from 23% to 28%. The HR-MS

data of compounds 5d–5f and 16b–16d are in agreement with

mono- and disubstitution, respectively. In addition, the ¹H NMR

spectra of 16b–16d showed signals for the proton at the 4-position

in the range of 6.5–6.6 ppm, which is consistent with the thiazol-

2(3H)-ylidene scaffold whereas the signals for the same proton in

the ¹H NMR spectra of compounds 5d–5f were at 6.9–7.0 ppm,

which indicates a thiazole ring system. Apparently the carbonyl

carbon of the N-acyl chloride reagents is sufﬁciently electrophilic

to allow nucleophilic attack both by the nitrogen of the amino

group at the 2-position and that at the 3-position of thiazole ring.

2.2. Biology

Using 41F5 (Fig. 1) as the template, our primary intention was

to develop an initial Histoplasma SAR for aminothiazole analogues

(Fig. 2) by mapping the molecular target’s binding pocket through

varying dimensions and basic properties of substituents at the 2-

and 5-positions of the aminothiazole core. Another objective was

to determine the general effect of substitution at the 3- and 4-posi-

tions of the ring system on activity. Some other substitution effects

were explored as well. For analogues with an Histoplasma MIC₅₀

In order to explore the effect of substituents at the N3 position

of the thioazole ring on Histoplasma growth inhibition, compound

4f was exposed to methyl iodide in the presence of sodium hydride

according to previously described methods (Scheme 2).^20,21Sur-

prisingly, the reaction produced a mixture of two products, 14b

and 16a, in 38% and 32% yield, respectively. Both compounds have

similar HR-MS data indicating mono-methylation. However, for

compound 16a, a high ﬁeld shift to 6.53 ppm was observed for

the proton at the 4-position in the ¹H NMR spectrum, presumably

due to lack of aromaticity in the thiazol-2(3H)-ylidene scaffold,

compared to ꢀ7.2 ppm for the same proton in 14b.

<3.5 lM, a very basic Cryptococcus SAR was also developed. In addi-

tion, for eleven compounds out of this group, we tested for poten-

tial liver toxicity in human hepatocyte HepG2 cells to establish

selectivity indices (SIs).

Table 1 and Figure 1 summarize the biological data of aminothi-

azole derivatives with a benzyl substituent at the 5-position and

various types of substituents at the 2-position. Within this group

of compounds, those with cyclohexylmethylamide- (4e) and cyclo-

hexylethylamide (4f) substituents at the 2-position had the lowest

In order to explore urea-type spacers and also the presence of

heteroatoms in the ring system of the 2-position side chain, the

reaction of compound 3a with various N-acyl chlorides was carried

out in the presence of DMAP (Scheme 3). In contrast to all reactions

Histoplasma MIC₅₀- (0.7 lM) and MIC (1.3–2.5 lM) values. Cyclo-

pentylamide- (4c), cyclohexylamide- (4d) and cyclobutylamide

(2F8, Fig. 1) substituents caused slightly lower activity

(MIC₅₀= 1.6–2.5

mide- (4b), tetrahydrothiopyran- (5a), and adamantylamide

groups had markedly reduced activity (MIC₅₀= 4.8–6.7 M;

MIC = 10–20 M). Interestingly, introduction of an E-ethene func-

lM; MIC = 5 lM), whereas those with isopropyla-

l

tion between the amide and the cyclohexyl group (4g) reduced

activity signiﬁcantly compared with a cyclohexylethyl group (4f).

Another noticeable ﬁnding was that the introduction of O- or N-

heteroatoms at various positions of the ring systems at the 2-posi-

tion reduced activity (5b–5h) even when the ring system was com-

parable in size to the cyclopentyl or cyclohexyl rings (5b–5f)

Scheme 2. Reagents and conditions: (a) MeI, NaH, THF, 2 h, rt.

(MIC₅₀>10 lM; MIC >20 lM). Other compounds in Table 1, that

is, 3a (unsubstituted 2-amino group), 4a (2-triﬂuoromethylamide

group) and 4h (5-phenylamide group) had MIC₅₀- and MIC values

>10 lM and >20 lM, respectively.

With the compounds shown in Table 2, we explored the effect

of substitution at the 5-benzyl group on anti-Histoplasma activity.

Scheme 3. Reagents and conditions: (a) 3-cyclohexylpropanoyl chloride, TEA, THF,

rt.

Figure 2. Basic Histoplasma SAR for aminothiazoles.

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

535

Table 1

5-Benzyl-substituted aminothiazole derivatives

Histoplasma capsulatum

Cryptococcus neoformans

HepG2 cells

SI (Histo/HepG2)

Compd

3a

R₄

H

R₅

R₁

H

R₂

MIC₅₀

>10

(l

M)

MIC (

>20

20

lM)

MIC₅₀

^and

nd

(

lM)

MIC (

nd

lM)

MIC₅₀

nd

(lM)

H

nd

4a

C(O)CF₃

C(O)CH(CH₃)₂

>10

nd

4b

6.7

nd

4c

4d

4e

4f

H

1.6 0.1

0.7 0.1

>10

5

3.6 0.9

1.3 0.2

>10

10

5

>40

nd

>24

>21

>44

nd

5

2.5

1.3

>20

nd

>10

4g

4h

nd

>10

nd

4i

H

5.0

10

nd

5a

5b

5c

5d

5e

5f

H

4.8

10

nd

>10

>20

5g

5h

H

>10

>20

nd

a

Not determined.

Aromatic ortho- (8a, 8b) and meta- (7b, 7c) substitution with ﬂuo-

rine and chlorine did not substantially alter activity compared with

unsubstituted 4c–4f (Table 1) whereas para-substitution (6a–6d)

had a negative impact. Noticeable is the lack of activity observed

for 7a with a triﬂuoromethyl group in meta-position.

Table 3 displays biological data for compounds with naphth-1-

ylmethyl- or naphth-2-ylmethyl group at the 5-position. Within

the group of aminothiazole derivatives with a naphth-1-ylmethyl

substituent, a similar trend was observed as for compounds with

5-benzyl substituent (Table 1). Compounds with cyclohexylamide-

(9d), cyclohexylmethylamide- (9e) and cyclohexylethylamide (9f)

groups at the 2-position had the lowest Histoplasma IC₅₀values

(MIC₅₀= 0.4 lM; MIC = 0.6–1.3 lM) whereas those with smaller

isopropylamide- (9b) and cyclopentylamide (9c) substituents had

slightly reduced activity. Triﬂuoromethylamide- (9a), phenyla-

mide- (9g) and adamantylamide (9h) substituents at the 2-posi-

tion caused markedly reduced activity (MIC₅₀>10

>20 M). Except for compounds 10a, with a 2-isopropylamide

group (MIC₅₀= 4.5 M; MIC = 20 M), and 10c, with 2-cyclohexyl-

ethylamide group (MIC₅₀= 5.7 M; MIC = 20 M), all aminothia-

zole derivatives with naphth-2-ylmethyl group at the

5-position had MIC₅₀values >10 M (MIC >20 M). Comparing

lM; MIC

l

a

l

naphth-1-ylmethyl substitution at the 5-position with benzyl sub-

stitution at the same position, the isopropylamide group at the

536

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

Table 2

5-Benzyl-substituted aminothiazoles with differing substitution pattern at the 5-benzyl group

Histoplasma capsulatum

Cryptococcus neoformans

HepG2 cells

SI Histo/HepG2)

Compd

R₄

H

R₅

R₃

H

R₄

MIC₅₀

5.2

(lM)

MIC (

lM)

MIC₅₀

^and

(

lM)

MIC (

l

M)

MIC₅₀

nd

(lM)

6a

20

nd

6b

6c

6d

H

4.4 1.0

>10

20

nd

>20

>10

7a

7b

7c

8a

8b

H

>10

>20

2.5

nd

65

57

nd

1.1 0.4

0.8 0.1

0.9 0.3

1.0 0.3

>10

>20

39

40

nd

2

a

Not determined.

2-position had a signiﬁcant impact on activity, as evidenced by an

MIC₅₀of 1.5 M (MIC = 2.5 M) for 9b vs. an MIC₅₀of 6.7

(MIC = 20 M) for 4b. Overall, compounds 9d–9f, with naphth-

1-ylmethyl substituent at the 5-position combined with cyclo-

hexylamide-, cyclohexylmethylamide-, and cyclohexylethylamide

substituents, respectively, at the 2-position, had the highest anti-

(15d, 15e, 15g, 15h) with MIC₅₀values ranging from 2.5

lM to

l

lM

7.4 M (MIC = 5–20 M). In contrast, compounds with 4-phenyl

l

group and hydrogen at the 5-position (15a, 15b) had no activity.

Disubstitution at the amide nitrogen (14b) as well as replacement

of thiazole with thiadiazole (14a), and possibly also thiophene

(4H2, Fig. 1), abolished or reduced activity. In addition, the simul-

taneous presence of a hydroxymethyl linker at the 5-position and

a Boc group at the 2-position (2a, Table 5) resulted in lack of

activity. Interestingly, compounds 15e–15h (Table 5) and 13b–

13e (Table 4) showed similar activity patterns. In both sub-series,

2-cyclohexylmethylamide substitution (13c, 15f) abolished activ-

ity whereas the cyclohexylamide- (13b, 15e), cyclohexylethyla-

mide- (13d, 15g), and phenyl (13e, 15h) homologues retained

activity.

Although only a very basic SAR was established for efﬁcacy

against Cryptococcus, we noted some similarities but also differ-

ences to the Histoplasma SAR. As in the case of the Histoplasma

SAR, compounds with cyclopentaneamide- (4c, 9c) and cyclohexa-

neamide groups (4d, 9d) at the 2-position had anti-Cryptococcus

activity. In contrast to the Histoplasma SAR, however, the com-

pounds with larger cyclohexylmethylamide- (4e, 9e) and cyclo-

hexylethylamide (4f, 9f) substituents had lost activity against

Cryptococcus. The same is the case for the smaller isopropyl group

(9b). At the 5-postion, the naphth-1-ylmethyl group (9c, 9d)

resulted in highest activity where as the benzyl- (4c, 4d) and phen-

ylethyl (11a) groups caused moderate loss of activity.

Histoplasma activities (MIC₅₀= 0.4 lM; MIC = 0.6–1.3 lM) of all

tested compounds.

The compounds presented in Table 4 were evaluated to deter-

mine the effect of phenylethyl-, phenyl-, and cyclohexylmethyl

substituents at the 5-position on Histoplasma growth. Phenylethyl-

(11a, 11b) substitution reduced activity only slightly compared to

naphth-1-ylmethyl substitution (9d–9f, Table 3) whereas phenyl

substitution (12b–12d) had a detrimental impact on activity. An

interesting pattern was observed for compounds with cyclo-

hexylmethyl substituent at the 5-position. Those with isopropyla-

mide- (13a), cyclohexylmethylamide- (13c), and adamantylamide

(13f) groups at the 2-position had no activity, whereas those with

phenylamide (13e) substituent retained some activity

(MIC₅₀= 4.6

(13b) and cyclohexylethylamide- (13d) substitution produced high

activity (MIC₅₀= 0.7–0.9 M; MIC = 2.5–5.0 M).

lM; MIC = 10 lM). In contrast, cyclohexylamide-

l

Biological data for compounds with varying substitution pat-

terns, including groups at the 3- or 4-position, are shown in

Table 5, Schemes 2, 3, and Figure 1. Compounds with substituents

at the 3- (16a–16d, Schemes 2 and 3 [data not shown]) and 4-

(14c, 15a–15h, Table 5) positions had reduced anti-Histoplasma

activity or were inactive. Some aminothiazole derivatives with

bulky adamantyl substitution at the 4-position in combination

with hydrogen at the 5-position retained moderate activity

SIs between >21(4d) and >100(9f) indicate generally low host

toxicity of the aminothiazole antifungals. Interestingly, commer-

cially-available compound 6d (Table 2) did not have any antifungal

activity against Histoplasma. However, the same compound caused

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

537

Table 3

5-Napthyl-substituted aminothiazole derivatives

Histoplasma capsulatum

Cryptococcus neoformans

HepG2 cells

SI (Histo/HepG2)

Compd

R₄

H

R₅

R₁

H

R₂

MIC₅₀

>10

(

lM)

MIC (

>20

lM)

MIC₅₀

^and

(l

M)

MIC (

lM)

MIC₅₀

nd

(lM)

9a

C(O)CF₃

nd

9b

H

C(O)CH(CH₃)₂

1.5 0.1

0.8 0.1

2.5

1.3

0.6

1.3

>20

>10

>20

1.3

0.6

>20

nd

9c

0.8 0.3

0.4 0.1

>10

>40

>57

97

9d (41F5)

0.4 0.01

0.4 0.02

>10

39

1

9e

9f

37

92

>10

>40

nd

>100

nd

9g

nd

9h

H

>10

4.5

>20

20

nd

10a

10b

10c

10d

10e

10f

C(O)CH(CH₃)₂

>10

5.7

>20

20

>10

>20

a

Not determined.

in vitro proliferation inhibition of DU-145 human prostate cancer

cells with an IC₅₀of 15 nM.¹⁵This compound, with host cell toxic-

ity but no antifungal activity, highlights the good speciﬁcity for

fungi of the aminothiazole analogues presented here.

3. Summary and conclusions

The Histoplasma SAR studies resulted in the lowest MIC₅₀and

MIC values (0.4 M; MIC = 0.6–1.3 M) for compounds 9d (41F5),

l

Most of the active aminothiazoles are very lipophilic and do not

contain functional groups that are ionizable under physiological

conditions. For example, 9d has a CLogP of 5.67 (ChemBioDraw

13.0.2.3020). Thus, in the case of some of the compounds that were

tested in more detail, slight (4c, 7c, 9d, 9e) to moderate (4e, 7b, 9c)

9e, and 9f. These compounds have a naphth-1-ylmethyl group at

the 5-position and a cyclohexylamide-, cyclohexylmethylamide-,

and cyclohexylethylamide substituent, respectively, at the 2-

position. The MIC values of these compounds are approximately

1–2 lM (Fig. 3), which is in the range of effective in vitro concen-

trations of some clinically established antifungal²²and antipara-

sitic drugs.²³The highest SI (>100) was observed for compound

9f. Overall, SIs ranged from >21 to >100, which indicates the pos-

sibility of low host toxicity of these novel aminothiazole antifun-

gals and signiﬁcant differences to, or even absence of, equivalent

precipitation at high compound concentrations (generally >40 lM)

was noticed during the antifungal assays in the test vials even

though the media contained 1% DMSO. Solubility could be

improved by increasing the DMSO concentrations. However, at

concentrations above 1%, DMSO itself inhibited fungal growth.

538

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

Table 4

Aminothiazole derivatives with phenylethyl,- phenyl-, and cyclohexylmethyl substituents at the 5 position

Histoplasma capsulatum

Cryptococcus neoformans

HepG2 cells

SI (Histo/HepG2)

Compd

11a

11b

12a

12b

12c

R₄

H

R₅

R₁

H

R₂

MIC₅₀

(

lM)

MIC (

l

M)

MIC₅₀

(

lM)

MIC (

lM)

MIC₅₀

^and

>40

nd

(lM)

0.9 0.1

0.7 0.1

>10

2.5

2.7 0.6

>10

nd

5

nd

>50

nd

2.5

>20

nd

>20

2.5

>10

nd

>10

nd

12d

13a

13b

13c

>10

nd

C(O)CH(CH₃)₂

>10

nd

0.7 0.1

>10

nd

>20

nd

>20

5

nd

13d

13e

0.8 0.1

4.6

9.6

>20

nd

10

nd

13f

H

>10

>20

nd

a

Not determined.

mammalian targets for the tested aminothiazole antifungals. This

hypothesis is also supported by the ﬁnding that compound 6d,

which is structurally related to 41F5, did not have antifungal activ-

ity although it proved to be a strong inhibitor of in vitro prolifera-

tion of DU-145 human prostate cancer cells.¹⁵It was previously

observed that 9d (41F5) has inhibitory rather than microbicidal

action.⁷It remains to be determined whether the newly tested

compounds have the same activity proﬁle.

4. Experimental methods

4.1. Chemistry

4.1.1. General chemical procedures

¹H and ¹³C NMR spectra were obtained on a Bruker DRX 400 at

The Ohio State University College of Pharmacy (400 MHz for ¹H

and 100 MHz for ¹³C). Chemical shifts (d) are reported in ppm from

internal deuterated chloroform or methanol. Coupling constants

are reported in Hz. ¹³C NMR spectra are fully decoupled. High res-

olution-electrospray ionization (HR-ESI) mass spectra were

obtained on a Micromass LCT spectrometer at The Ohio State Uni-

versity Campus Chemical Instrumentation Center, Columbus, OH.

Silica gel 60 (0.063–0.200 mm), used for gravity column chroma-

tography, and silica gel 60 (0.015–0.049 mm), used for ﬂash col-

umn chromatography, were purchased from Dynamic Adsorbents

Inc., Norcross, USA. Reagent-grade solvents were used for column

chromatography. Pre-coated aluminum-backed TLC plates with sil-

ica gel 60 F254 (0.25-mm layer thickness) from Sigma-Aldrich

were used for TLC. Compound visualization for TLC was achieved

by UV light. Anhydrous solvents, starting materials, including

compounds 1a, 1b, 3m, 3n, and 3o, and other chemicals were pur-

chased from standard commercial suppliers. 3-(2-Furyl)-N-[5-(4-

methoxybenzyl)-1,3-thiazol-2-yl]acrylamide (6d) was purchased

from Chembridge, San Diego, CA, USA. Compounds 3c, 3d, 4b, 4d,

6a, 6b, 9b, 9d, 12a, 12b, 14a, and 15b are commercially available.

However, no synthetic procedures and analytical data are pub-

lished. These compounds were synthesized and analyzed as

described in Sections 4.1.3. and 4.1.4. Compounds 2f,²⁵3a,²⁶

Previous studies have shown that 9d (41F5) does not inhibit

the in vitro growth of Candida albicans, Aspergillus fumigatus,

and Blastomyces dermatitidis.⁷Strikingly, 9d (41F5), and to a

slightly lesser extend 9c, have antifungal activity against two

phylogenetically diverged organisms, that is, the basidiomycete

Cryptococcus and the ascomycete Histoplasma, yet there are sub-

tle differences in the SARs of these fungi. We suspect that

aminothiazoles target a common molecule in both fungal spe-

cies, but that the binding site has diverged between members

of different phyla within the kingdom Fungi. This suggests the

possibility that this class of antifungals has potential to inhibit

the same molecular target also in other fungal pathogens (e.g.,

Candida, Aspergillus, or Blastomyces) based on appropriate struc-

tural modiﬁcations. Preliminary studies indicate that there is

no synergism beyond additive effects between 9d (41F5) and

ﬂuconazole (fractional inhibitory concentration index [FIC]

ꢀ0.7), nor between 9d (41F5) and caspofungin (FIC ꢀ1.1) sug-

gesting that the aminothiazole antifungal target is not involved

in ergosterol biosynthesis or cell wall b-glucan synthesis.²⁴Thus,

the possibility of a new molecular target in the area of fungal

therapy seems likely, warranting further investigation.

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

539

Table 5

Aminothiazole derivatives with varying substitution patterns

Histoplasma capsulatum

Cryptococcus neoformans

Compd

X

C

R₄

H

R₅

R₁

H

R₂

MIC₅₀

>10

(lM)

MIC (

lM)

MIC₅₀

^and

(lM)

MIC (

lM)

2a

C(O)OC(CH₃)₃

>20

nd

14a

14b

14c

15a

15b

N

C

_

H

>10

>20

nd

H

Me

H

Me

H

15c

15d

15e

15f

C

H

C(O)CH(CH₃)₂

>10

7.4

>20

20

5

nd

>20

nd

20

2.5 0.1

>10

nd

>20

20

10

15g

15h

5.2

nd

3.1 0.1

8.3

a

Not determined.

3b,²⁷3e,¹⁵3f,²⁵3g,²⁸3h,²⁸3i,²⁹3j,²⁹3k,¹⁸3l,¹⁸4h,³⁰15a,²⁰and

15h³¹are commercially available and/or have been reported

before. These compounds were synthesized and analyzed as

described in Sections 4.1.2., 4.1.3. and 4.1.4. using partially differ-

ent methods as described previously. Compound 3p was prepared

according to a procedure described by Hardgrave et al.³²(2E)-3-

Cyclohexyl-2-propenoic acid, used for the synthesis of 4g, was pre-

pared according to procedures previously described.³³All reactions

were carried under Argon atmosphere.

4.1.2.2. tert-Butyl{5-[hydroxy(naphthalen-1-yl)methyl]thiazol-

2-yl}carbamate (2b). White solid; R_f0.55 (DCM/MeOH, 19:1);

yield 30%. ¹H NMR (400 MHz, CDCl₃): d 11.71 (br s, 1H), 7.97 (m,

1H), 7.82 (m, 3H), 7.46 (m, 3H), 6.95 (s, 1H), 6.67 (s, 1H), 2.21 (s,

1H), 1.34 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): d 162.0, 137.7,

135.0, 134.4, 134.0, 130.3, 129.0, 126.5, 125.9, 125.5, 123.8,

123.6, 82.0, 67.8, 28.2. MS (HR-ESI) for C₁₉H₂₀N₂OSNa [(M+Na)⁺],

calcd: m/z 379.1092, found: m/z 379.1089.

4.1.2.3. tert-Butyl-{5-[hydroxy(naphthalen-2-yl)methyl]thiazol-

2-yl}carbamate (2c). White solid; R_f0.54 (DCM/MeOH, 19:1);

yield 30%. NMR (400 MHz, CDCl₃): d 11.83 (s, 1H), 7.93 (s, 1H),

7.84 (m, 3H), 7.49 (m, 3H), 7.06 (s, 1H), 6.14 (s, 1H), 2.17 (s, 1H),

1.39 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): d 162.4, 139.7, 135.1,

134.6, 133.3, 128.7, 128.3, 127.8, 126.5, 126.4, 124.9, 124.3, 82.2,

70.7, 28.2. MS (HR-ESI) for C₁₉H₂₀N₂O₃SNa [(M+Na)⁺], calcd: m/z

379.1092, found: m/z 379.1087.

4.1.2. General procedure for the synthesis of compounds 2a–2l

n-BuLi (2.5 M in THF, 1.4 equiv) was added drop wise to a mix-

ture of compound 1a or 1b (1 equiv) and aldehyde (1.2 equiv) in

THF (ꢀ20 mL) at À78 °C for 2 h. The reaction was quenched by

adding a saturated aqueous solution of NH₄Cl, extracted with

EtOAc, washed with water and then brine. The organic phase was

dried over anhydrous Na₂SO₄, evaporated, and the residue was

puriﬁed by silica gel column chromatography.

4.1.2.4. tert-Butyl-{5-[hydroxy(cyclohexyl)methyl]thiazol-2-yl}-

carbamate (2d). White solid; R_f0.35 (DCM/MeOH, 9:1); yield

4.1.2.1. tert-Butyl{5-[hydroxy(phenyl)methyl]thiazol-2-yl}car-

bamate (2a). White solid; R_f0.49 (DCM/MeOH, 19:1); yield

59%. ¹H NMR (400 MHz, CDCl₃): d 7.29–7.48 (m, 5H), 7.07 (s, 1H),

6.01 (s, 1H), 2.20 (s, 1H), 1.48 (s, 9H). ¹³C NMR (100 MHz, CDCl₃):

d 162.3, 152.8, 142.3, 135.2, 134.2, 128.8, 128.3, 126.2, 82.3, 70.6,

38%. ¹H NMR (400 MHz, CDCl₃):

d 7.20 (s, 1H), 4.61 (d,

J = 6.83 Hz, 1H), 2.03 (m, 1H), 1.64–1.79 (m, 5H), 1.59 (s, 9H),

0.98–1.29 (m, 5H). ¹³C NMR (100 MHz, CDCl₃): d 161.8, 152.7,

134.4, 132.3, 82.7, 73.2, 45.2, 29.3, 29.0, 28.4, 26.0. MS (HR-ESI)

for C₁₅H₂₄N₂O₃SNa [(M+Na)⁺], calcd: m/z 335.1405, found: m/z

335.1397.

28.3. MS (HR-ESI) for

329.0936, found: m/z 329.0917.

C

₁₅H₁₈N₂O₃SNa [(M+Na)⁺], calcd: m/z

540

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

4.1.2.8. tert-Butyl-{5-[hydroxy(3-ﬂuorophenyl)methyl]thiazol-

2-yl}carbamate (2h). White solid; R_f0.5 (DCM/MeOH, 19:1);

yield 58%. ¹H NMR (400 MHz, CDCl₃): d 11.68 (br s, 1H), 7.34 (m,

1H), 7.22 (m, 2H), 7.14 (s, 1H), 7.03 (m, 1H), 6.0 (s, 1H), 2.19 (s,

1H), 1.52 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): d 164.3, 162.5,

161.9, 144.9, 134.6, 130.3, 121.8, 115.3, 115.0, 113.4, 113.2, 82.3,

69.9, 28.3. MS (HR-ESI) for C₁₅H₁₇FN₂OS [(M+H)⁺], calcd: m/z

347.0842, found: m/z 347.0845.

4.1.2.9. tert-Butyl-{5-[hydroxyl(2-ﬂuorophenyl)methyl]thiazol-

2-yl}carbamate (2i). White solid; R_f0.51 (DCM/MeOH, 19:1);

yield 46%. ¹H NMR (400 MHz, CDCl₃): d 11.95 (s, 1H), 7.64 (t,

J = 7.61 Hz, 1H), 7.29–7.35 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.03–

7.10 (m, 2H), 6.29 (s, 1H), 1.51 (s, 9H). ¹³C NMR (100 MHz, CDCl₃):

d 162.3, 161.0, 158.5, 152.9, 134.4, 133.8, 124.7, 124.6, 115.7,

115.5, 82.1, 64.7, 28.3. MS (HR-ESI) for C₁₅H₁₇FN₂O₃S [(M+H)⁺],

calcd: m/z 325.1022, found: m/z 325.1024.

4.1.2.10. tert-Butyl-{5-[hydroxyl(2-chlorophenyl)methyl]thia-

zol-2-yl}carbamate (2j). White solid; R_f0.49 (DCM/MeOH,

19:1); yield 48%. ¹H NMR (400 MHz, CDCl₃): d 11.97 (s, 1H), 7.81

(m, 1H), 7.33–7.44 (m, 2H), 7.21–7.32 (m, 1H), 7.09 (s, 1H), 6.41

(s, 1H), 1.52 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): d 162.3, 152.9,

139.9, 134.9, 133.3, 132.1, 129.7, 129.3, 127.5, 127.5, 82.2, 67.2,

28.3. MS (HR-ESI) for

C

₁₅H₁₇ClN₂O₃S [(M+Na)⁺], calcd: m/z

363.0546, found: m/z 363.0551.

4.1.2.11. tert-Butyl-{5-[1-hydroxyl(2-phenyl)ethyl]thiazol-2-yl}-

carbamate (2k). White solid; R_f0.47 (DCM/MeOH, 19:1); yield

35%. ¹H NMR (400 MHz, CDCl₃): d 7.19–7.30 (m, 5H), 7.07 (s, 1H),

5.11 (t, J = 6.5 Hz, 1H), 3.13 (d, J = 6.8 Hz, 2H), 1.56 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃): d 161.5, 152.9, 137.3, 134.3, 133.5, 129.6,

128.8, 127.1, 82.3, 69.6, 45.7, 28.4. MS (HR-ESI) for C₁₆H₂₀N₂O3S

[(M+Na)⁺], calcd: m/z 343.1092, found: m/z 343.1082.

4.1.2.12. tert-Butyl-{5-[hydroxy(phenyl)methyl]-4-methylthia-

zol-2-yl}carbamate (2l). White solid; R_f0.53 (DCM/MeOH,

19:1); yield 22%. ¹H NMR (400 MHz, CDCl₃): d 7.31–7.44 (m, 5H),

6.03 (s, 1H), 2.29 (s, 3H), 2.01 (s, 1H), 1.51 (s, 9H). ¹³C NMR

(100 MHz, CDCl₃): d 160.0, 152.6, 143.1, 142.9, 128.7, 128.3,

128.0, 126.0, 82.6, 69.6, 28.3, 15.1. MS (HR-ESI) for C₁₆H₂₀N₂O₃S

[(M+Na)⁺], calcd: m/z 343.1092, found: m/z 343.1102.

Figure 3. Dose-response curves for compounds 9d–9f against Histoplasma capsu-

latum yeasts.

4.1.2.5. tert-Butyl-{5-[hydroxy-(4-ﬂuorophenyl)methyl]thiazol-

2-yl}carbamate (2e). White solid; R_f0.5 (DCM/MeOH, 19:1);

yield 46%. ¹H NMR (400 MHz, CDCl₃): d 11.85 (br s, 1H), 7.44 (m,

2H), 7.04–7.09 (m, 2H), 6.0 (s, 1H), 2.19 (s, 1H) 1.51 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃): d 168.7, 159.4, 143.5, 140.1, 139.4, 132.9,

119.3, 118.9, 82.7, 69.1, 24.3. MS (HR-ESI) for C₁₈H₂₂N₂OSNa

[(M+Na)⁺], calcd: m/z 347.0842, found: m/z 347.0839.

4.1.3. General procedure of the synthesis of compounds 3a–3l

A

mixture of compounds 2a–2l (1 equiv), triethylsilane

(8 equiv), and TFA (14 equiv) in DCM (ꢀ20 mL) was stirred over-

night at room temperature. The mixture was evaporated and the

residue was treated with a saturated solution of aqueous NaHCO₃.

The aqueous layer was extracted with DCM, dried over anhydrous

Na₂SO₄, ﬁltered, and evaporated. The residue was puriﬁed by silica

gel column chromatography.

4.1.2.6. tert-Butyl-{5-[hydroxy(3-triﬂuoromethylphenyl)methyl]-

thiazol-2-yl}carbamate (2f). White solid; R_f0.52 (DCM/MeOH,

19:1); yield 31%. ¹H NMR (400 MHz, CDCl₃): d 11.95 (br s, 1H),

7.75 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.04 (s,

1H), 6.08 (s, 1H), 1.49 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): d

163.0, 153.13, 143.6, 134.9, 134.6, 131.6, 131.2, 129.9, 129.5,

125.3, 123.3, 82.6, 70.1, 28.5. MS (HR-ESI) for C₁₆H₁₇F₃N₂O₃S

[(M+Na)⁺], calcd: m/z 397.0812, found: m/z 397.0810.

4.1.3.1. 5-Benzyl-2-thiazolamine (3a). White solid; R_f0.38

(DCM/MeOH, 19:1); yield 71%. ¹H NMR (400 MHz, CDCl₃): d

7.18–7.34 (m, 5H), 6.78 (s, 1H), 4.92 (br s, 2H), 3.88 (s, 2H). ¹³C

NMR (100 MHz, CDCl₃): d 167.5, 139.9, 135.7, 128.7, 128.5, 128.2,

126.8, 33.5. MS (HR-ESI) for

C

₁₀H₁₀N₂S [(M)⁺], calcd: m/z

191.0643, found: m/z 191.0618.

4.1.2.7. tert-Butyl-{5-[hydroxy(3-chlorophenyl)methyl]thiazol-

2-yl)carbamate (2g). White solid; R_f0.51 (DCM/MeOH, 19:1);

yield 53%.¹H NMR (400 MHz, CDCl₃): d 11.91 (s, 1H), 7.39 (s, 1H),

7.33 (m, 3H), 6.01 (s, 1H), 2.19 (s, 1H), 1.49 (s, 9H). ¹³C NMR

(100 MHz, CDCl₃): d 162.6, 152.9, 144.4, 134.7, 134.6, 134.5,

130.0, 128.4, 126.4, 124.4, 82.3, 69.9, 28.3. MS (HR-ESI) for

4.1.3.2. 5-(1-Naphthalenylmethyl)-2-thiazolamine (3b). White

solid; R_f0.42 (DCM/MeOH, 19:1); yield 60%. ¹H NMR (400 MHz,

CDCl₃): d 8.03 (m, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.49 (m, 2H),

7.41 (m, 1H), 7.28 (m, 1H), 6.71 (s, 1H), 6.47 (br s, 2H), 4.31 (s,

2H). ¹³C NMR (100 MHz, CDCl₃): d 168.2, 134.4, 134.1, 131.6,

129.0, 128.2, 126.9, 126.6, 126.1, 125.7, 123.6, 30.8. MS (HR-ESI)

for C₁₄H₁₂N₂S [(M+H)⁺], calcd: m/z 241.0799, found: m/z 241.0803.

C

₁₅H₁₇ClN₂O₃S [(M+Na)⁺], calcd: m/z 363.0546, found: m/z

363.0547.

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

541

4.1.3.3. 5-(2-Naphthalenylmethyl)-2-thiazolamine (3c). White

solid; R_f0.45 (DCM/MeOH, 19:1); yield 53%. ¹H NMR (400 MHz,

CDCl₃): d 7.79–7.83 (m, 3H), 7.67 (s, 1H), 7.47 (m, 2H), 7.36 (d,

J = 7.4 Hz, 1H), 6.87 (s, 1H), 4.82 (br s, 2H), 4.13 (s, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 167.4, 137.4, 136.0, 133.7, 132.5, 128.4,

127.8, 127.0, 126.8, 126.3, 125.8, 33.7. MS (HR-ESI) for C₁₄H₁₂N₂S

[(M+H)⁺], calcd: m/z 241.0799, found: m/z 241.0796.

4.1.3.12. 5-Benzyl-4-methyl-2-thiazolamine (3l). White solid;

R_f0.4 (DCM/MeOH, 19:1); yield 81%. ¹H NMR (400 MHz, CDCl₃):

d 7.21–7.28 (m, 5H), 4.83 (br s, 2H), 3.91 (s, 2H), 2.17 (s, 3H). ¹³C

NMR (100 MHz, CDCl₃): d 164.9, 143.6, 140.4, 128.7, 128.2, 126.6,

120.1, 32.3, 14.9 MS (HR-ESI) for C₁₁H₁₂N₂S [(M+H)⁺], calcd: m/z

205.0799, found: m/z 205.0789.

4.1.4. General procedure for the synthesis of compounds 4b–4f,

4h, 4i, 5h, 6a–6c, 7a–7c, 8a, 8b, 9b–9h, 10a–10f, 11a, 11b, 12a–

12d, 13a–13f, 14a, 14c, and 15a–15h

To a mixture of compounds 3a–3p (1 equiv) and acid chloride

(1 equiv) in THF (ꢀ20 mL), triethylamine (3 equiv) was added.

The mixture was stirred at room temperature for 15 min followed

by ﬁltration. The solvents were evaporated and the residue was

puriﬁed by column chromatography.

4.1.3.4. 5-(Cyclohexylmethyl)-2-thiazolamine (3d). White solid;

R_f0.31 (DCM/MeOH, 19:1); yield 91%. ¹H NMR (400 MHz, CDCl₃): d

6.69 (s, 1H), 4.92 (br s, 2H), 2.51 (d, J = 7.0 Hz, 2H), 1.67 (m, 5H), 1.43

(m, 1H), 1.09–1.32 (m, 3H), 0.91–1.04 (m, 2H). ¹³C NMR (100 MHz,

CDCl₃): d 166.7, 135.5, 128.0, 39.7, 35.0, 33.0, 26.5, 26.3. MS (HR-

ESI) for C₁₀H₁₆N₂O [(M+H)⁺], calcd: m/z 197.1112, found: m/z

197.1104.

4.1.3.5. 5-(4-Fluorobenzyl)-2-thiazolamine (3e). White solid;

R_f0.39 (DCM/MeOH, 19:1); yield 77%. ¹H NMR (400 MHz, CDCl₃):

d 7.21 (m, 2H), 7.03 (m, 2H), 6.78 (s, 1H), 4.83 (br s, 2H), 3.88 (s,

2H). ¹³C NMR (100 MHz, CDCl₃): d 168.9, 164.5, 162.0, 137.1,

131.1, 129.5, 117.0, 34.1 MS (HR-ESI) for C₁₀H₉FN₂S [(M+H)⁺],

calcd: m/z 209.0549, found: m/z 209.0546.

4.1.4.1. N-(5-Benzylthiazol-2-yl)isobutyramide (4b). White solid;

R_f0.5 (DCM); yield 61%. ¹H NMR (400 MHz, CDCl₃): d 11.70 (s, 1H),

7.24–7.33 (m, 5H), 7.11 (s, 1H), 4.11 (s, 2H), 2.69 (m, 1H), 1.28 (s,

3H), 1.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): d 175.1, 159.3, 139.5,

133.3, 132.3, 128.9, 128.6, 126.9, 35.4, 33.2, 19.4. MS (HR-ESI) for

C

₁₄H₁₆N₂OSNa [(M+Na)⁺], calcd: m/z 283.0881, found: m/z 283.0881.

4.1.3.6. 5-[3-(Triﬂuoromethyl)benzyl]-2-thiazolamine (3f). White

solid; R_f0.38 (DCM/MeOH, 19:1); yield 55%. ¹H NMR (400 MHz,

CDCl₃): d 7.41–7.53 (m, 4H), 6.79 (s, 1H), 5.21 (br s, 2H), 4.03 (s,

2H). ¹³C NMR (100 MHz, CDCl₃): d 168.0, 140.8, 136.24, 131.9,

131.2, 130.9, 129.2, 126.5, 125.2, 123.7, 33.2. MS (HR-ESI) for

4.1.4.2. N-(5-Benzylthiazol-2-yl)cyclopentanecarboxamide (4c).

White solid; R_f0.53 (DCM); yield 60%. ¹H NMR (400 MHz, CDCl₃):

d 11.82 (s, 1H), 7.25–7.34 (m, 5H), 7.06 (s, 1H,), 4.10 (s, 2H), 2.82

(m, 1H), 1.90–1.95 (m, 4H), 1.78–1.80 (m, 2H), 1.62–1.65 (m, 2H).

¹³C NMR (100 MHz, CDCl₃):

d

174.4, 159.4, 139.4, 133.2,

132.2, 128.9, 128.6, 126.9, 45.5, 33.2, 30.5, 26.1. MS (HR-ESI) for

₁₆H₁₈N₂OSNa [(M+Na)⁺], calcd: m/z 309.1038, found: m/z

C

₁₁H₉F₃N₂S [(M+H)⁺], calcd: m/z 259.0504, found: m/z 259.0517.

C

4.1.3.7. 5-(3-Chlorobenzyl)-2-thiazolamine (3g). White solid;

R_f0.37 (DCM/MeOH, 19:1); yield 77%. ¹H NMR (400 MHz, CDCl₃):

d 7.22 (m, 3H), 7.08 (s, 1H), 5.02 (br s, 2H), 4.01 (s, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 167.7, 141.9, 136.2, 134.5, 129.9, 128.6,

127.0, 126.6, 33.1. MS (HR-ESI) for C₁₀H₉ClN₂S [(M+H)⁺], calcd:

m/z 225.0253, found: m/z 225.0252.

309.1037.

4.1.4.3. N-(5-Benzylthiazol-2-yl)cyclohexanecarboxamide (4d).

White solid; R_f0.52 (DCM); yield 66%. ¹H NMR (400 MHz, CDCl₃): d

11.97 (s, 1H), 7.24–7.32 (m, 5H), 7.05 (s, 1H), 4.08 (s, 2H), 2.33 (m,

1H), 1.81–1.93 (m, 4H), 1.71 (m, 1H), 1.52–1.64 (m, 2H), 1.15–1.28

(m, 3H). ¹³C NMR (100 MHz, CDCl₃): d 174.4, 159.5, 139.2, 133.1,

132.2, 128.9, 128.8, 126.9, 44.9, 33.2, 29.2, 25.7. MS (HR-ESI) for

4.1.3.8. 5-(3-Fluorobenzyl)-2-thiazolamine (3h). White solid;

R_f0.39 (DCM/MeOH, 19:1); yield 75%. ¹H NMR (400 MHz, CDCl₃):

d 7.24–7.31 (m, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.90–6.97 (m, 2H),

6.83 (s, 1H), 4.98 (br s, 2H), 3.97 (s, 2H). ¹³C NMR (100 MHz,

CDCl₃): d 167.9, 164.6, 142.7, 136.5, 130.4, 127.4, 124.3, 115.8,

114.0, 33.4 MS (HR-ESI) for C₁₀H₉FN₂S [(M+H)⁺], calcd: m/z

209.0549, found: m/z 209.0547.

C

₁₇H₂₀N₂OSNa [(M+Na)⁺], calcd: m/z 323.1194, found: m/z

323.1115.

4.1.4.4. N-(5-Benzylthiazol-2-yl)-2-cyclohexylacetamide (4e).

White solid; R_f0.51 (DCM); Yield 71%. ¹H NMR (400 MHz,

CDCl₃): d 11.69 (s, 1H), 7.18–7.33 (m, 5H), 7.08 (s, 1H), 4.10 (s,

2H), 2.32 (d, 1H, J = 7.13 Hz), 1.73–1.89 (m, 5H,), 0.91–1.34 (m, 6H).

¹³C NMR (100 MHz, CDCl₃): d 170.6, 159.3, 139.2, 132.6, 132.2,

128.9, 128.7, 127.0, 44.3, 35.3, 33.2, 26.3, 26.2, 26.1 MS (HR-ESI) for

4.1.3.9. 5-(2-Fluorobenzyl)-2-thiazolamine (3i). White solid; R_f

0.38 (DCM/MeOH, 19:1) yield 82%. ¹H NMR (400 MHz, CDCl₃): d

7.19 (m, 2H), 7.01–7.09 (m, 2H), 6.78 (s, 1H), 4.92 (br s, 2H), 4.03

(s, 2H). ¹³C NMR (100 MHz, CDCl₃): d 167.4, 162.0, 159.5, 136.2,

128.6, 126.5, 124.4, 115.6, 115.4, 26.4. MS (HR-ESI) for C₁₀H₉FN₂S

[(M+Na)⁺], calcd: m/z 231.0368, found: m/z 231.0359.

C

₁₈H₂₂N₂OSNa [(M+Na)⁺], calcd: m/z 337.1350, found: m/z

337.1366.

4.1.4.5. N-(5-Benzylthiazol-2-yl)-3-cyclohexylpropanamide (4f).

White solid; R_f0.55 (DCM); yield 71%. ¹H NMR (400 MHz, CDCl₃): d

7.21–7.29 (m, 5H), 7.07 (s, 1H), 4.13 (s, 2H), 2.51 (t, J = 7.9 Hz, 2H),

1.57–1.73 (m, 7H), 1.16–1.31 (m, 4H), 0.91–1.03 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 179.8, 171.7, 138.9, 132.2, 131.4, 128.9,

128.6, 127.1, 37.4, 37.3, 32.3, 26.7, 26.6, 26.4, 26.3. MS (HR-ESI)

4.1.3.10. 5-(2-Chlorobenzyl)-2-thiazolamine (3j). White solid;

R_f0.38 (DCM/MeOH, 19:1); yield 77%. ¹H NMR (400 MHz, CDCl₃):

d 7.39 (m, 1H), 7.19–7.33 (m, 3H), 6.82 (s, 1H), 4.94 (br s, 2H),

4.11 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): d 167.5, 137.6, 136.4,

133.8, 130.4, 129.7, 128.3, 127.2, 126.1, 31.0. MS (HR-ESI) for C_10-

H₉ClN₂S [(M+H)⁺], calcd: m/z 225.0253, found: m/z 225.0192.

for

C

₁₉H₂₄N₂OS [(M+H)⁺], calcd: m/z 329.1688, found: m/z

329.1686.

4.1.3.11. 5-Phenethyl-2-thiazolamine (3k). White solid; R_f0.38

(DCM/MeOH, 19:1); yield 61%. ¹H NMR (400 MHz, CDCl₃): d 7.33

(m, 2H), 7.24 (m, 3H), 6.67 (s,1H), 4.98(br s, 2H), 2.81–2.93 (m,

4H). ¹³C NMR (100 MHz, CDCl₃): d 166.9, 140.8, 134.7, 128.6,

4.1.4.6. N-(5-Benzylthiazol-2-yl)benzamide (4h). White solid;

R_f0.71 (DCM); yield 63%. ¹H NMR (400 MHz, CDCl₃): d 7.96 and

7.21–7.64 (m, 10H), 6.78 (s, 1H), 4.06 (s, 2H). ¹³C NMR (100 MHz,

CDCl₃): d 165.6, 159.4, 139.4, 133.9, 132.8, 129.1, 128.9, 128.8,

128.7, 128.6, 128.1, 126.9, 33.1. MS (HR-ESI) for C₁₇H₁₄N₂OSNa

[(M+Na)⁺], calcd: m/z 317.0724, found: m/z 317.0740.

128.5, 128.2, 126.3, 37.6, 29.1. MS (HR-ESI) for

C₁₁H₁₂N₂S

[(M+H)⁺], calcd: m/z 205.0799, found: m/z 205.0801.

542

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

4.1.4.7. N-(5-Benzylthiazol-2-yl)adamantane-1-carboxamide (4i).

White solid; R_f0.49 (DCM); yield 66%. ¹H NMR (400 MHz, CDCl₃): d

9.84 (s, 1H), 7.21–7.35 (m, 5H), 4.11 (s, 2H), 2.14 (m, 3H), 1.91 (m,

6H), 1.73 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): 175.8, 158.4, 139.5,

133.8, 132.3, 128.8, 128.6, 126.9, 41.2, 38.9, 36.5, 33.1, 28.1. MS

(HR-ESI) for C₂₁H₂₄N₂OSNa [(M+Na)⁺], calcd: m/z 375.1507, found:

m/z 375.1515.

(m, 1H), 6.92 (m, 2H), 4.06 (s, 2H), 2.5 (t, J = 7.7 Hz, 2H), 1.70 (m,

7H), 1.12–1.19 (m, 4H), 0.91–0.99 (m, 2H). ¹³C NMR (100 MHz,

CDCl₃): d 171.7, 164.4, 161.9, 159.8, 141.8, 133.3, 131.1, 130.3,

124.2, 115.5, 114.0, 37.4, 33.8, 33.1, 32.8, 32.5, 26.6, 26.3. MS

(HR-ESI) for C₁₉H₂₃FN₂OS [(M+Na)⁺], calcd: m/z 369.1413, found:

m/z 369.1413.

4.1.4.15. N-[5-(2-Chlorobenzyl)thiazol-2-yl]-3-cyclohexanepro-

panamide (8a). White solid; R_f0.53 (DCM); yield 76%.¹H NMR

(400 MHz, CDCl₃): d 12.01 (br s, 1H), 7.44 (m, 1H), 7.28 (m, 1H),

7.21 (m, 2H), 7.14 (s, 1H), 4.17 (s, 2H), 2.52 (t, J = 7.6 Hz, 2H),

1.61–1.69 (m, 7H), 1.23–1.31 (m, 4H), 0.91 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 171.6, 159.2, 156.6, 137.2, 134.0, 133.7,

130.7, 129.9, 128.5, 127.3, 37.4, 33.8, 33.2, 32.5, 30.8, 26.6, 26.3.

MS (HR-ESI) for C₁₉H₂₃ClN₂OS [(M+H)⁺], calcd: m/z 363.1298,

found: m/z 363.1299.

4.1.4.8. N-(5-Benzylthiazol-2-yl)-2-(thiophen-2-yl)thiazole-5-car-

boxamide (5h). White solid; R_f0.58 (hexanes/EtOAc, 7:1); yield

65%.¹H NMR (400 MHz, CDCl₃): d 10.43 (br s, 1H), 8.19 (s, 1H), 7.61

(d, J = 3.5 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.24–7.41 (m, 6H), 7.12

(d, J = 3.6 Hz, 1H), 4.11 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): d

157.9, 156.5, 148.3, 139.5, 136.0, 135.2, 133.1, 129.3, 128.9,

128.7, 128.2, 128.1, 126.9, 33.2. MS (HR-ESI) for C₁₈H₁₃N₃OS₃[(-

M+Na)⁺], calcd: m/z 406.0118, found: m/z 406.0156.

4.1.4.9. N-[5-(4-Fluorobenzyl)thiazol-2-yl]cyclopentanecarbox-

amide (6a). White solid; R_f0.47 (DCM); yield 75%. ¹H NMR

(400 MHz, CDCl₃): d 11.83 (s, 1H), 7.18–7.21 (m, 2H), 6.96–7.03

(m, 3H), 4.03 (s, 2H), 2.8 (m, 1H), 1.92 (m, 4H), 1.77–1.79 (m,

2H), 1.60–1.63 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 174.5,

163.1, 160.7, 136.2, 133.2, 132.1, 130.1, 115.7 45.5, 32.4, 30.5,

4.1.4.16.

3-Cyclohexyl-N-[5-(2-ﬂuorobenzyl)thiazol-2-yl]pro-

panamide (8b). White solid; R_f0.49 (DCM); yield 67%. ¹H NMR

(400 MHz, CDCl₃): d 11.91 (s, 1H), 7.34 (m, 2H), 7.01–7.09 (m,

3H), 4.11 (s, 2H), 2.49 (m, 2H), 1.51–1.68 (m, 7H), 1.11–1.23 (m,

4H), 0.92–0.99 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 171.8,

162.3, 159.5, 133.7, 130.9, 129.1, 126.7, 124.7, 116.0, 115.8, 37.6,

34.1, 33.4, 33.3, 32.8, 26.9, 26.6. MS (HR-ESI) for C₁₉H₂₃FN₂OS

[(M+Na)⁺], calcd: m/z 369.1413, found: m/z 369.1404.

26.1. MS (HR-ESI) for

327.0943, found: m/z 327.0933.

C

₁₆H₁₇FN₂OS [(M+Na)⁺], calcd: m/z

4.1.4.17. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]isobutyramide

(9b). White solid; R_f0.55 (DCM); yield 74%.¹H NMR (400 MHz,

CDCl₃): d 12.01 (s, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.83 (m, 1H),

7.37–7.49 (m, 4H), 7.01 (s, 1H), 4.52 (s, 2H), 2.61 (m, 1H), 1.17 and

1.19(d s, 6H). ¹³C NMR (100 MHz, CDCl₃): d 175.2, 159.2, 135.2,

134.1, 133.4, 132.0, 131.7, 129.0, 128.0, 126.9, 126.4, 125.9, 125.7,

123.7, 35.2, 30.6, 19.3. MS (HR-ESI) for C₁₈H₁₈N₂OSNa [(M+Na)⁺],

calcd: m/z 333.1038, found: m/z 333.1044.

4.1.4.10. N-[5-(4-Fluorobenzyl)thiazol-2-yl]cyclohexanecarbox-

amide (6b). White solid; R_f0.43 (DCM); yield 78%. ¹H NMR

(400 MHz, CDCl₃): d 12.02 (s, 1H), 7.2–7.26 (m, 2H), 6.97–7.02

(m, 3H), 4.05 (s, 2H), 2.36 (m, 1H), 1.79–1.89 (m, 4H), 1.67 (m,

1H), 1.49–1.62 (m, 2H), 1.11–1.30 (m, 4H). ¹³C NMR (100 MHz,

CDCl₃): d 174.3, 163.2, 160.7, 135.0, 133.2, 132.1, 130.3, 115.6,

45.0, 32.4, 29.2, 28.3, 25.7. MS (HR-ESI) for

C₁₇H₁₉FN₂OS

[(M+Na)⁺], calcd: m/z 341.1100, found: m/z 341.1080.

4.1.4.18. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]cyclopentane-

carboxamide (9c). White solid; R_f0.52 (DCM); yield 68%. ¹H

NMR (400 MHz, CDCl₃): d 11.93 (s, 1H), 8.02 (m, 1H), 7.91 (m,

1H), 7.79 (m, 1H), 7.38–7.51 (m, 4H), 7.03 (s, 1H), 4.54 (s, 2H),

2.71 (m, 1H), 1.69–1.77 (m, 6H), 1.53 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 174.4, 159.1, 135.1, 134.2, 133.4, 131.9,

131.7, 129.0, 128.0, 126.4, 125.9, 125.7, 123.8, 45.4, 30.6, 30.4,

4.1.4.11. N-[5-(4-Fluorobenzyl)thiazol-2-yl]-3-cyclohexanepro-

panamide (6c). White solid; R_f0.44 (DCM); yield 66%.¹H NMR

(400 MHz, CDCl₃): d 12.11 (br s, 1H), 7.22 (m, 2H), 7.01 (m, 3H),

4.03 (s, 2H), 2.51 (m, 2H), 1.59–1.73 (m, 6H), 1.12–1.31 (m, 5H),

0.84–1.03 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): d 171.7, 163.1,

160.6, 135.0, 132.9, 131.9, 130.1, 115.7, 37.3, 33.8, 33.1, 32.5,

32.2, 26.6, 26.3. MS (HR-ESI) for C₁₉H₂₃FN₂OS [(M+Na)⁺], calcd:

m/z 369.1413, found: m/z 369.1427.

26.0. MS (HR-ESI) for

359.1194, found: m/z 359.1200.

C

₂₀H₂₀N₂OSNa [(M+Na)⁺], calcd: m/z

4.1.4.12. N-{5-[3-(Triﬂuoromethyl)benzyl]thiazol-2-yl}-3-cyclo-

hexanepropanamide (7a). White solid; R_f0.49 (DCM); yield

80%. ¹H NMR (400 MHz, CDCl₃): d 12.31 (br s, 1H), 7.39–7.52 (m,

4H), 7.11 (s, 1H), 4.08 (s. 2H), 2.51 (t, J = 8.0 Hz, 2H), 1.61–1.73

(m, 7H), 1.11–1.38 (m, 4H), 0.91–1.02 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 171.7, 159.8, 140.3, 133.5, 132.0, 131.4,

131.1, 130.8, 129.3, 125.3, 123.9, 37.4, 33.8, 33.1, 32.9, 32.5, 26.6,

4.1.4.19. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]cyclohexane-

carboxamide (9d). White solid; R_f0.53 (DCM); yield 63%.¹H

NMR (400 MHz, CDCl₃): d 12.33 (s, 1H), 8.04 (m, 1H), 7.93 (m,

1H), 7.81 (m, 1H), 7.44–7.48 (m, 4H), 6.81 (s, 1H), 4.53 (s, 2H),

2.21 (m, 1H), 1.69 (m, 2H), 1.41–1.77 (m, 5H), 1.11 (m, 1H), 0.83

(m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 174.4, 159.3, 134.9, 134.2,

133.3, 131.7, 128.9, 127.2, 126.4, 125.9, 125.7, 123.9, 44.8, 30.5,

29.1, 25.6, 25.5. MS (HR-ESI) for C₂₁H₂₂N₂OS [(M+H)⁺], calcd: m/z

351.1531, found: m/z 351.1539.

26.3. MS (HR-ESI) for

419.1378, found: m/z 419.1381.

C

₂₀H₂₃F₃N₂OS [(M+Na)⁺], calcd: m/z

4.1.4.13. N-[5-(3-Chlorobenzyl)thiazol-2-yl]-3-cyclohexanepro-

panamide (7b). White solid; R_f0.55 (DCM); yield 71%. ¹H NMR

(400 MHz, CDCl₃): d 12.36 (s, 1H), 7.24 (m, 3H), 7.13 (m, 2H),

4.07 (s, 2H), 2.5 (t, J = 7.6 Hz, 2H), 1.62–1.72 (m, 7H), 1.14–1.26

(m, 4H), 0.91–0.96 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 171.7,

159.8, 134.7, 133.3, 131.0, 130.1, 128.7, 127.2, 126.7, 37.4, 33.8,

33.1, 32.7, 32.5, 26.6, 26.4, 26.3. MS (HR-ESI) for C₁₉H₂₃ClN₂OS

[(M+H)⁺], calcd: m/z 363.1298, found: m/z 363.1302.

4.1.4.20. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]-2-cyclohexa-

neacetamide (9e). White solid; R_f0.54 (DCM); yield 71%. ¹H

NMR (400 MHz, CDCl₃): d 12.26 (s, 1H), 8.03 (m, 1H), 7.81–7.89

(m, 1H), 7.82 (m, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 6.91 (s, 1H),

4.53 (s, 2H), 2.21 (d, J = 7.25 Hz, 2H), 1.81 (m, 1H), 1.63 (m, 5H),

1.01–1.23 (m, 3H), 0.84 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d

170.6, 159.1, 134.9, 134.2, 133.3, 131.7, 129.0, 128.0, 127.1,

126.4, 126.0, 125.7, 123.8, 44.1, 35.2, 33.1, 30.5, 26.2, 26.0. MS

(HR-ESI) for C₂₂H₂₄N₂OSNa [(M+Na)⁺], calcd: m/z 387.1507, found:

m/z 387.1499.

4.1.4.14. 3-Cyclohexane-N-[5-(3-ﬂuorobenzyl)thiazol-2-yl]-pro-

panamide (7c). White solid; R_f0.51 (DCM); yield 64%. ¹H NMR

(400 MHz, CDCl₃): d 12.37 (s, 1H), 7.32 (m, 1H), 7.13 (s, 1H), 7.01

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

543

4.1.4.21. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]-3-cyclohex-

anepropanamide (9f). White solid; R_f0.56 (DCM); yield 67%. ¹H

NMR (400 MHz, CDCl₃): d 8.01 (m, 1H), 7.94 (m, 1H), 7.82 (m, 1H),

7.39–7.49 (m, 4H), 7.03 (s, 1H), 4.54 (s, 2H), 2.42 (t, J = 7.8 Hz, 2H),

1.51–1.73 (m, 7H), 1.21 (m, 4H), 0.94 (m, 2H). ¹³C NMR (100 MHz,

CDCl₃): d 171.7, 159.4, 134.7, 134.2, 131.9, 131.6, 129.1, 128.2,

127.0, 126.5, 126.0, 125.7, 123.6, 37.2, 33.7, 33.1, 32.3, 30.5, 26.6,

125.9, 37.3, 33.8, 33.3, 33.1, 32.5, 26.6, 26.2. MS (HR-ESI) for C_23-

H₂₆N₂OSNa [(M+Na)⁺], calcd: m/z 401.1668, found: m/z 401.1658.

4.1.4.28. N-[5-(2-Naphthalenylmethyl)thiazol-2-yl]benzamide

(10e). White solid; R_f0.56 (DCM); yield 72%.¹H NMR

(400 MHz, CDCl₃): d 12.53 (br s, 1H), 7.91–8.03 (m, 2H), 7.81 (m,

3H), 7.78 (s, 1H), 7.54 (m, 2H), 7.31 (m, 3H), 6.67 (s, 1H), 4.21 (s,

2H). ¹³C NMR (100 MHz, CDCl₃): d 167.2, 161.0, 138.2, 135.6,

135.1, 134.7, 134.2, 134.0, 133.9, 133.5, 131.5, 130.0, 129.5,

129.2, 128.5, 127.8, 127.3, 34.6. MS (HR-ESI) for C₂₁H₁₆N₂OSNa

[(M+Na)⁺], calcd: m/z 367.0881, found: m/z 367.0898.

26.2. MS (HR-ESI) for

401.1668, found: m/z 401.1675.

C

₂₃H₂₆N₂OSNa [(M+Na)⁺], calcd: m/z

4.1.4.22. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]benzamide

(9g). White solid; R_f0.65 (DCM); yield 59%. ¹H NMR (400 MHz,

CDCl₃): d 12.68 (s, 1H), 7.93–87.99 (m, 2H), 7.81 (m, 3H), 7.53

(m, 2H), 7.32–7.44 (m, 3H), 7.12–7.23 (m, 2H), 6.41 (s, 1H), 4.49

(s, 2H). ¹³C NMR (100 MHz, CDCl₃): d 166.1, 159.3, 135.0, 134.4,

134.2, 133.0, 132.5, 131.7, 129.0, 128.6, 128.1, 128.0, 127.1,

126.4, 125.9, 125.7, 123.9, 30.5. MS (HR-ESI) for C₂₁H₁₆N₂OS

[(M+H)⁺], calcd: m/z 345.1062, found: m/z 345.1067.

4.1.4.29. N-[5-(2-Naphthalenylmethyl)thiazol-2-yl)adamantane-

1-carboxamide (10f). White solid; R_f0.64 (DCM); yield 77%.¹H

NMR (400 MHz, CDCl₃): d 9.73 (s, 1H), 7.81 (m, 3H), 7.70 (s, 1H),

7.43–7.51 (m 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.21 (s, 1H), 4.22 (s,

2H), 2.18 (m, 3H), 2.01 (s, 1H), 1.89 (s, 5H), 1.74 (m, 6H). ¹³C

NMR (100 MHz, CDCl₃): d175.7, 158.4, 137.0, 134.1, 133.7, 132.5,

132.2, 128.6, 127.8, 127.0, 126.3, 125.8, 41.1, 38.9, 36.4, 33.3,

4.1.4.23. N-[5-(1-Naphthalenylmethyl)thiazol-2-yl]adamantane-

1-carboxamide (9h). White solid; R_f0.55 (DCM); yield 65%.¹H

NMR (400 MHz, CDCl₃): d 9.78 (s, 1H), 8.03 (m, 1H), 7.88 (m, 1H),

7.83 (m, 1H), 7.42–7.53 (m, 4H), 7.11 (s, 1H), 4.53 (s, 2H), 2.01

(m, 3H), 1.93 (m, 6H), 1.72 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): d

175.8, 158.1, 135.2, 134.1, 132.0, 131.7, 128.9, 127.9, 127.0,

126.4, 125.9, 125.7, 123.8, 41.1, 38.8, 36.4, 30.5, 28.0. MS (HR-

ESI) for C₂₅H₂₆N₂OSNa [(M+Na)⁺], calcd: m/z 425.1664, found: m/

z 425.1667.

28.0. MS (HR-ESI) for

C

₂₅H₂₆N₂OSNa [(M+Na)⁺], calcd: m/z

425.1664, found: m/z 425.1672.

4.1.4.30. N-(5-Phenethylthiazol-2-yl)cyclopentanecarboxamide

(11a). White solid; R_f0.45 (DCM); yield 71%. ¹H NMR

(400 MHz, CDCl₃): d 12.11 (s, 1H), 7.33 (m, 2H), 7.21 (m, 3H),

6.93 (s, 1H), 3.12 (m, 2H), 3.01 (m, 2H), 2.85 (m, 1H), 1.91 (m,

4H), 1.82 (m, 2H), 1.61 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d

174.5, 158.8, 140.6, 132.5, 131.9, 128.6, 126.4, 45.4, 37.6, 30.5,

28.7, 26.2. MS (HR-ESI) for C₁₇H₂₀N₂OS [(M+Na)⁺], calcd: m/z

323.1194, found: m/z 323.1148.

4.1.4.24. N-(5-(2-Naphthalenylmethyl)thiazol-2-yl]isobutyramide

(10a). White solid; R_f0.55 (DCM); yield 64%. ¹H NMR (400 MHz,

CDCl₃): d 12.03 (br s, 1H), 7.84 (m, 3H), 7.67 (s, 1H), 7.41–7.53 (m,

2H), 7.41 (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), 7.21 (s, 1H), 4.32 (s, 2H),

2.71 (m, 1H), 1.26 (s, 3H), 1.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃):

d 175.2, 160.0, 137.0, 133.7, 133.2, 132.5, 132.1, 128.6, 127.8,

126.9, 126.4, 125.9, 36.7, 34.7, 20.8. MS (HR-ESI) for C₁₈H₁₈N₂OSNa

[(M+Na)⁺], calcd: m/z 333.1038, found: m/z 333.1034.

4.1.4.31. N-(5-Phenethylthiazol-2-yl)-3-cyclohexanepropanamide

(11b). White solid; R_f0.47 (DCM); yield 79%. ¹H NMR (400 MHz,

CDCl₃): d 12.24 (s, 1H), 7.21–7.33 (m, 5H), 7.03 (s, 1H), 3.11 (m,

2H), 3.01 (m, 2H), 2.53 (t, J = 7.6 Hz), 1.59–1.73 (m, 7H), 1.11–

1.31 (m, 4H), 0.89–1.03 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d

171.6, 158.7, 140.6, 132.7, 132.0, 128.5, 126.5, 37.6, 37.4, 33.8,

33.2, 32.6, 28.8, 26.6, 26.3. MS (HR-ESI) for C₂₀H₂₆N₂OS [(M+H)⁺],

calcd: m/z 365.1664, found: m/z 365.1664.

4.1.4.25. N-[5-(2-Naphthalenylmethyl)thiazol-2-yl]cyclohexan-

ecarboxamide (10b). White solid; R_f0.52 (DCM); yield 69%.¹H

NMR (400 MHz, CDCl₃): d 12.22, (br s, 1H), 7.81 (m, 3H), 7.74 (s,

1H), 7.52 (m, 2H), 7.32 (m, 1H), 7.04 (s, 1H), 4.21 (s, 2H), 2.33

(m, 1H), 1.76 (m, 2H), 1.70 (m, 2H), 1.51 (m, 3H), 1.03–1.21 (m,

3H). ¹³C NMR (100 MHz, CDCl₃): d 174.4, 159.8, 136.3, 133.7,

132.6, 132.2, 132.0, 128.7, 127.8, 127.7, 127.2, 127.0, 126.4,

125.9, 44.9, 33.3, 29.2, 25.6. MS (HR-ESI) for C₂₁H₂₂N₂OSNa

[(M+Na)⁺], calcd: m/z 373.1351, found: m/z 373.1364.

4.1.4.32. N-(5-Phenylthiazol-2-yl)cyclopentanecarboxamide (12a).

White solid; R_f0.43 (DCM); yield 75%. ¹H NMR (400 MHz, CDCl₃): d

12.52 (s, 1H), 7.62 (m, 3H), 7.43 (t, J = 7.7 Hz, 2H), 7.31 (m, 1H),

3.01 (m, 1H), 2.05 (m, 4H), 1.78 (m, 2H), 1.70 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 174.8, 159.5, 132.9, 131.9, 131.4, 129.3, 128.0,

126.3, 45.5, 30.6, 26.2. MS (HR-ESI) for C₁₅H₁₆N₂OS[(M+Na)⁺],

calcd: m/z 295.0881, found: m/z 295.0886.

4.1.4.26. N-[5-(2-Naphthalenylmethyl)thiazol-2-yl]-2-cyclohexa-

neacetamide (10c). White solid; R_f0.53 (DCM); yield 78%. ¹H

NMR (400 MHz, CDCl₃): d 12.12 (s, 1H), 7.81 (m, 3H), 7.68 (s,

1H), 7.51 (m, 2H), 7.35 (d, J = 8.9, 1H), 7.09 (s, 1H), 4.21 (s, 2H),

2.31 (d, J = 7.2 Hz, 2H), 1.83 (m, 1H), 1.81–1.93 (m, 5H), 1.22 (m,

2H), 1.01 (m, 1H), 0.93 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d

170.7, 159.6, 136.4, 133.7, 132.6, 132.1, 128.7, 127.8, 127.1,

126.9, 126.4, 125.9, 44.2, 35.2, 33.3, 33.2, 26.2, 26.0. MS (HR-ESI)

for C₂₂H₂₄N₂OSNa [(M+Na)⁺], calcd: m/z 387.1507, found: m/z

387.1502.

4.1.4.33. N-(5-Phenylthiazol-2-yl)cyclohexanecarboxamide (12b).

White solid; R_f0.41 (DCM); yield 69%. ¹H NMR (400 MHz, CDCl₃): d

12.33 (s, 1H), 7.51 (m, 2H), 7.43 (m, 2H), 7.30 (m, 1H), 2.53 (m, 1H),

2.01 (m, 2H), 1.89 (m, 2H), 1.61–1.78 (m, 3H), 1.19–1.51 (m, 3H).

¹³C NMR (100 MHz, CDCl₃): d 174.5, 159.4, 132.9, 131.8, 131.5,

129.3, 128.0, 126.2, 45.0, 29.3, 25.9, 25.7. MS (HR-ESI) for C₁₆H_18-

N₂OS [(M+H)⁺], calcd: m/z 309.1038, found: m/z 309.1037.

4.1.4.34. N-(5-Phenylthiazol-2-yl)-2-cyclohexaneacetamide (12c).

White solid; R_f0.43 (DCM); yield 78%. ¹H NMR (400 MHz, CDCl₃): d

12.39 (s, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 6.8 Hz,

1H), 7.32 (t, J = 7.6 Hz, 1H), 2.50 (d, J = 7.12 Hz, 2H), 2.0 (m, 1H),

1.84 (d, J = 12.27 Hz, 2H), 1.72 (m, 3H), 1.01–1.39 (m, 6H). ¹³C NMR

(100 MHz, CDCl₃): d 170.8, 159.2, 132.9, 131.6, 131.5, 129.3, 128.1,

126.3, 44.3, 36.4, 33.4, 26.2, 26.1. MS (HR-ESI) for C₁₇H₂₀N_2-

OS[(M+Na)⁺], calcd: m/z 323.1194, found: m/z 323.1182.

4.1.4.27. N-[5-(2-Naphthalenylmethyl)thiazol-2-yl)-3-cyclohex-

anepropanamide (10d). White solid; R_f0.54 (DCM); yield

76%.¹H NMR (400 MHz, CDCl₃): d 12.17 (s, 1H), 7.82 (m, 3H), 7.72

(s, 1H), 7.49 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 4.21 (s,

2H), 2.53 (t, J = 7.6 Hz, 2H), 1.62–1.73 (m, 7H), 1.14–1.21 (m, 4H),

0.91 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 171.16, 159.5, 136.8,

133.7, 133.1, 132.5, 132.0, 128.6, 127.8, 127.0, 126.9, 126.4,

544

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

4.1.4.35. N-(5-Phenylthiazol-2-yl)-3-cyclohexanepropanamide

(12d). White solid; R_f0.45 (DCM); yield 66%. ¹H NMR

(400 MHz, CDCl₃): d 12.61 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 7.7 Hz,

2H), 7.43 (t, J = 7.8 Hz, 2H), 7.31 (m, 1H), 2.55 (t, J = 7.9 Hz, 2H),

1.61–1.84 (m, 7H), 1.09–1.41 (m, 4H), 0.89–1.02 (m, 2H). ¹³C

NMR (100 MHz, CDCl₃): d 171.8, 159.5, 132.8, 131.6, 131.4, 129.3,

128.0, 126.2, 37.5, 34.0, 33.2, 32.6, 26.6, 26.3. MS (HR-ESI) for C_18-

H₁₃N₂OS [(M+H)⁺], calcd: m/z 315.1531, found: m/z 315.1517.

(m, 2H).¹³C NMR (100 MHz, CDCl₃): d 172.6, 164.1, 161.3, 137.1,

129.1, 128.9, 127.6, 37.4, 36.4, 34.0, 33.1, 32.7, 32.1, 29.8, 26.7,

26.4. MS (HR-ESI) for

C

₁₈H₂₃N₃OS [(M+Na)⁺], calcd: m/z

352.1455, found: m/z 352.1460.

4.1.4.43. N-(5-Benzyl-4-methylthiazol-2-yl)-3-cyclohexylpropan-

amide (14c). White solid; R_f0.5 (DCM); yield 51%. ¹H NMR

(400 MHz, CDCl₃): d 7.21–7.33 (m, 5H), 4.0 (s, 2H), 2.41 (t,

J = 7.8 Hz, 2H), 2.31 (s, 3H), 1.63–1.71 (m, 6H), 1.22–1.34 (m, 4H),

0.90 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 170.7, 155.3, 141.8,

139.8, 128.8, 128.4, 126.8, 124.8, 37.2, 34.0, 33.1, 32.6 32.2, 29.9,

26.6, 26.3, 14.8. MS (HR-ESI) for C₂₀H₂₆N₂OS [(M+Na)⁺], calcd: m/

z 365.1664, found: m/z 365.1665.

4.1.4.36. N-[5-(Cyclohexylmethyl)thiazol-2-yl]isobutyramide (13a).

White solid; R_f0.33 (DCM); yield 61%.¹H NMR (400 MHz, CDCl₃): d

12.08 (br s, 1H), 7.01 (s, 1H), 2.73 (m, 1H), 2.60 (d, J = 7.01 Hz, 2H),

1.68–1.76 (m, 4H), 1.52 (m, 1H), 1.17–1.28 (m, 10H), 0.90–0.99 (m,

2H). ¹³C NMR (100 MHz, CDCl₃): d 175.2, 158.8, 133.0, 131.7, 39.8,

35.4, 34.6, 33.1, 26.5, 26.3, 19.4. MS (HR-ESI) for C₁₄H₂₂N₂OSNa

[(M+Na)⁺], calcd: m/z 289.1351, found: m/z 289.1352.

4.1.4.44. N-(4-Phenylthiazol-2-yl)cyclopentanecarboxamide (15a).

White solid; R_f0.44 (DCM); yield 63%. ¹H NMR (400 MHz, CDCl₃): d

11.10 (s, 1H), 7.81 (d, J = 7.1, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t,

J = 7.1, 1H), 7.11 (s, 1H), 2.32 (m, 1H), 1.54 (m, 4H), 1.51 (m, 2H),

1.34 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 175.1, 159.8, 149.9,

134.5, 129.1, 128.4, 126.4, 108.0, 45.3, 30.4, 25.9. MS (HR-ESI) for

4.1.4.37. N-[5-(Cyclohexylmethyl)thiazol-2-yl]cyclohexanecarb-

oxamide (13b). White solid; R_f0.32 (DCM); yield 64%. ¹H NMR

(400 MHz, CDCl₃): d 12.08 (s, 1H), 7.01 (s, 1H), 2.73 (d, J = 6.9 Hz,

2H), 2.43 (m, 1H), 1.78–2.02 (m, 4H), 1.51–1.79 (m, 8H), 1.11–

1.29 (m, 7H), 1.0 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 174.4,

158.8, 133.0, 131.6, 45.0, 39.7, 34.6, 33.1, 29.8, 29.3, 26.5, 26.3,

C

₁₈H₂₂N₂OSNa [(M+Na)⁺], calcd: m/z 295.0881, found: m/z

295.0887.

25.8. MS (HR-ESI) for

C

₁₇H₂₆N₂OSNa [(M+Na)⁺], calcd: m/z

4.1.4.45. N-(4-Phenylthiazol-2-yl)-3-cyclohexanepropanamide

329.1664, found: m/z 329.1661.

(15b).

White solid; R_f0.46 (DCM); yield 59%. ¹H NMR

(400 MHz, CDCl₃): d 11.43 (s, 1H), 7.81 (d, J = 6.5 Hz, 2H),7.43 (t,

J = 7.5 Hz, 2H), 7.31 (t, J = 6.5 Hz, 1H), 7.19 (s, 1H), 2.01 (t,

J = 7.7 Hz, 2H), 1.63 (m, 3H), 1.31–1.40 (m, 4H), 1.11 (m, 3H),

0.83 (m, 1H), 0.69 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 172.1,

159.9, 149.6, 134.4, 129.1, 128.5, 126.3, 107.9, 37.1, 33.5, 32.8,

32.0, 26.5, 26.3. MS (HR-ESI) for C₁₈H₂₂N₂OSNa [(M+Na)⁺], calcd:

m/z 337.1351, found: m/z 337.1338.

4.1.4.38. N-[5-(Cyclohexylmethyl)thiazol-2-yl]-2-cyclohexaneace-

tamide (13c). White solid; R_f0.35 (DCM); yield 64%. ¹H NMR

(400 MHz, CDCl₃): d 12.19 (br s, 1H), 7.03 (s, 1H), 2.62 (d,

J = 7.2 Hz, 2H), 2.39 (d, J = 6.7 Hz, 2H), 1.89 (m, 1H), 1.61–1.84

(m, 10H), 1.51 (m, 1H), 1.09–1.31 (m, 6H), 0.91–0.99 (m, 4H). ¹³C

NMR (100 MHz, CDCl₃): d 170.7, 158.7, 133.0, 131.6, 44.3, 39.7,

35.4, 34.6, 33.3, 33.2, 33.1, 26.5, 26.3, 26.1. MS (HR-ESI) for C₁₈H_28-

N₂OSNa [(M+Na)⁺], calcd: m/z 343.1820, found: m/z 343.1820.

4.1.4.46. N-[4-(Adamantan-1-yl)thiazol-2-yl]isobutyramide (15c).

White solid; R_f0.5 (DCM); yield 65%. ¹H NMR (400 MHz, CDCl₃): d

8.81 (br s, 1H), 6.53 (s, 1H), 2.59 (m, 1H), 2.09 (m, 3H), 1.92 (m, 6H),

1.74 (m, 6H), 1.31 (d, J = 7.3 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃): d

174.3, 161.3, 157.0, 106.2, 42.2, 36.9, 26.3, 35.8, 29.8, 28.1, 19.3. MS

(HR-ESI) for C₁₇H₂₄N₂OSNa [(M+Na)⁺], calcd: m/z 327.1507, found:

m/z 327.1505.

4.1.4.39. N-[5-(Cyclohexylmethyl)thiazol-2-yl]-3-cyclohexanepro-

panamide (13d). White solid; R_f0.36 (DCM); yield 60%.¹H NMR

(400 MHz, CDCl₃): d 12.29 (br s, 1H), 7.03 (s, 1H), 2.62 (d, J = 7.0 Hz,

2H), 2.52 (t, J = 7.6 Hz, 2H), 1.57–1.69 (m, 11H), 1.53 (m, 1H), 1.22–

1.31 (m, 8H), 0.89–1.0 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): d 171.6,

158.8, 133.0, 131.6, 39.7, 37.5, 34.6, 33.9, 33.2, 33.1, 32.7, 26.7,

26.5, 26.3, 26.2. MS (HR-ESI) for C₁₉H₃₀N₂OSNa [(M+Na)⁺], calcd:

m/z 335.2157, found: m/z 335.2164.

4.1.4.47. N-[4-(Adamantan-1-yl)thiazol-2-yl]cyclopentanecarb-

oxamide (15d). White solid; R_f0.53 (DCM); yield 79%. ¹H NMR

(400 MHz, CDCl₃): d 8.91 (br s, 1H), 6.53 (s, 1H), 2.67 (m, 1H),

2.08 (m, 3H), 1.93 (m, 10H), 1.81 (m, 8H), 1.63 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 173.7, 161.2, 157.2, 106.0, 45.8, 42.2, 36.9,

36.3, 30.4, 28.7, 26.1. MS (HR-ESI) for C₁₉H₂₆N₂OSNa [(M+Na)⁺],

calcd: m/z 353.1664, found: m/z 353.1675.

4.1.4.40. N-[5-(Cyclohexylmethyl)thiazol-2-yl]benzamide (13e).

White solid; R_f0.45 (DCM); yield 65%. ¹H NMR (400 MHz, CDCl₃): d

8.11 (d, J = 7.5 Hz, 2H), 7.57 (m, 1H), 7.51 (m, 2H), 2.63 (d,

J = 7.1 Hz, 2H), 1.71–1.84 (m, 4H), 1.52 (m, 1H), 1.11–1.29 (m, 4H),

0.92–1.0 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 165.7, 158.9, 133.7,

132.7, 130.1, 128.9, 128.5, 128.2, 39.7, 34.5, 33.1, 26.5, 26.3. MS

(HR-ESI) for C₁₇H₂₀N₂OSNa [(M+Na)⁺], calcd: m/z 323.1194, found:

m/z 323.1197.

4.1.4.48. N-[4-(Adamantan-1-yl)thiazol-2-yl]cyclohexanecarb-

oxamide (15e). White solid; R_f0.55 (DCM); yield 61%. ¹H NMR

(400 MHz, CDCl₃): d 9.33 (br s, 1H), 6.51 (s, 1H), 2.32 (m, 1H),

1.83–2.11 (m, 20 H), 1.65–1.55 (m, 2H), 1.31 (m, 3H). ¹³C NMR

(100 MHz, CDCl₃): d 173.6, 161.1, 157.5, 105.0, 45.3, 42.1, 36.9,

4.1.4.41. N-[5-(Cyclohexylmethyl)thiazol-2-yl]adamantane-1-car-

boxamide (13f). White solid; R_f0.34 (DCM); yield 72%.¹H NMR

(400 MHz, CDCl₃): d 7.11 (s, 1H), 2.61 (d, J = 6.97 Hz, 2H), 2.11

(m, 3H), 1.93 (m, 6H), 1.62–1.84 (m, 9H), 1.22–1.33 (m, 6H),

0.81–1.0 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): d 175.9, 158.3,

131.9, 131.3, 41.3, 39.7, 38.9, 36.4, 34.5, 33.0, 28.0, 26.4, 26.2. MS

(HR-ESI) for C₂₁H₃₀N₂OSNa [(M+Na)⁺], calcd: m/z 381.1977, found:

m/z 381.1970.

36.3, 29.4, 28.7, 25.7, 25.6. MS (HR-ESI) for

C₂₀H₂₈N₂OSNa

[(M+Na)⁺], calcd: m/z 367.1820, found: m/z 367.1823.

4.1.4.49. N-[4-(Adamantan-1-yl)thiazol-2-yl]-2-cyclohexylaceta-

mide (15f). White solid; R_f0.54 (DCM); yield 68%. ¹H NMR

(400 MHz, CDCl₃): d 9.01 (s, 1H), 6.53 (s, 1H), 2.28 (s, 2H), 2.11

(s, 3H), 1.87 (s, 6H), 1.76 (m, 14H), 1.31 (m, 3H). ¹³C NMR

(100 MHz, CDCl₃): d 172.7, 164.0, 159.9, 107.8, 47.4, 45.0, 39.7,

39.1, 38.2, 36.0, 31.5, 28.9, 25.6. MS (HR-ESI) for C₂₁H₃₀N₂OSNa

[(M+Na)⁺], calcd: m/z 381.1977, found: m/z 381.1989.

4.1.4.42. N-(5-Benzyl-1,3,4-thiadiazol-2-yl)-3-cyclohexylpropan-

amide (14a). White solid; R_f0.56 (DCM); yield 85%. ¹H NMR

(400 MHz, CDCl₃): d 13.21 (s, 1H), 7.29–7.40 (m, 5H), 4.31 (s,

2H), 2.83 (m, 2H), 1.57–1.80 (m, 7H), 1.11–1.41 (m, 5H), 0.90–1.0

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

545

4.1.4.50. N-[4-(Adamantan-1-yl)thiazol-2-yl]-3-cyclohexylpropan-

amide (15g). White solid; R_f0.51 (DCM); yield 72%. ¹H NMR

(400 MHz, CDCl₃): d 9.33 (s, 1H), 6.51 (s, 1H), 2.44 (t, J = 8.1

Hz,2H), 2.11 (s, 3H), 1.91 (m, 6H), 1.64–1.79 (m, 12 H), 1.21–1.29

(m, 5H), 0.82–0.99 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 171.0,

161.1, 157.5, 105.0, 42.1, 36.9, 36.3, 34.1, 33.1, 32.5, 28.9, 26.5,

7.21 (m, 3H), 7.03 (s, 1H), 4.09 (s, 1H), 2.71 (m, 2H), 2.53 (m,

2H), 2.38 (m, 2H), 2.19 (m, 1H), 1.91–2.03 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 172.9, 159.5, 139.0, 133.0, 132.9, 129.0,

128.7, 127.1, 44.4, 33.2, 30.0, 27.8. MS (HR-ESI) for C₁₆H₁₈N₂OS₂

[(M+H)⁺], calcd: m/z 341.0758, found: m/z 341.0745.

26.3. MS (HR-ESI) for

395.2133, found: m/z 395.2143.

C

₂₂H₃₂N₂OSNa [(M+Na)⁺], calcd: m/z

4.1.6.3. N-(5-Benzylthiazol-2-yl)tetrahydro-2H-pyran-4-carbox-

amide (5b). White solid; R_f0.49 (DCM/MeOH, 19:1); yield 40%.

¹H NMR (400 MHz, CDCl₃): d 12.13 (s, 1H), 7.33–7.41 (m, 2H),

7.22 (m, 3H), 7.02 (s, 1H), 4.11 (s, 2H), 4.04 (d, J = 10.9 Hz, 2H),

3.33 (t, J = 10.9 Hz, 2H), 2.61–2.73 (m, 1H), 1.88–2.02 (m, 2H),

1.70 (d, J = 13.0 Hz, 2H) ¹³C NMR (100 MHz, CDCl₃): d 172.6,

159.4, 139.1, 132.9, 132.8, 129.0, 128.7, 127.1, 67.1, 41.88, 33.2,

4.1.4.51. N-[4-(Adamantan-1-yl)thiazol-2-yl]benzamide (15h).

White solid; R_f0.64 (DCM); yield 65%. ¹H NMR (400 MHz,

CDCl₃): d 8.01 (d, J = 7,2 Hz, 2H), 7.41–7.63 (m, 3H), 6.61 (s, 1H),

2.07 (m, 3H), 2.01 (m, 6H), 1.83 (m, 6H). ¹³C NMR (100 MHz,

CDCl₃): d 164.6, 161.4, 157.9, 132.9, 132.4, 129.1, 127.6, 106.5,

42.14, 37.0, 36.4 28.7. MS (HR-ESI) for C₂₀H₂₂N₂OSNa [(M+Na)⁺],

calcd: m/z 361.1351, found: m/z 361.1350.

28.8. MS (HR-ESI) for

C

₁₆H₁₈N₂O₂S [(M+Na)⁺], calcd: m/z

325.0987, found: m/z 325.0976.

4.1.6.4. N-(5-Benzylthiazol-2-yl)-1-methylpiperidine-4-carbox-

amide (5c). White solid; R_f0.53 (DCM/MeOH, 4:1); yield 20%.

¹H NMR (400 MHz, CD₃OD): d 7.21–7.34 (m, 5H), 7.11 (s, 1H),

4.03 (s, 2H), 2.91 (m, 2H), 2.48 (m, 1H), 2.31 (s, 3H), 2.11–2.21

(m, 2H), 1.78–1.91 (m, 4H). ¹³C NMR (100 MHz, CD₃OD): d 175.0,

159.3, 141.4, 135.4, 133.9, 129.8, 129.5, 127.8, 55.8, 46.3, 42.6,

33.7, 29.2. MS (HR-ESI) for C₁₇H₂₁N₃OS [(M+H)⁺], calcd: m/z

316.1484, found: m/z 316.1479.

4.1.5. General procedure for the synthesis of compounds 4a and

9a

TFAA (1.4 equiv) was added drop wise to a solution of com-

pound 3a or 3b (1 equiv) in DCM (3 mL) at 0 °C. The reaction mix-

ture was stirred at room temperature for 30 min. Subsequently, the

solvent was evaporated, the residue treated with a saturated aque-

ous solution of NaHCO₃, extracted with EtOAc, and washed with

water and then brine. The organic layer was dried over anhydrous

Na₂SO₄and concentrated in vacuo. The residue was puriﬁed by sil-

ica gel column chromatography.

4.1.6.5. N-(5-Benzylthiazol-2-yl)chromane-3-carboxamide (5g).

White solid; R_f0.73 (DCM/MeOH, 97:3); yield 21%. ¹H NMR

(400 MHz, CDCl₃): d 7.01–7.31 (m, 8H), 6.93 (m, 2H), 4.49 (m, 1H),

4.21 (t, J = 10.1 Hz, 1H), 4.01 (s, 2H), 3.23–3.31 (m, 1H), 3.11–3.219

(m, 1H), 3.0 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): d 171.3, 168.8,

159.9, 155.4, 140.7, 134.7, 134.4, 131.3, 129.9, 129.3, 128.4, 122.6,

121.6, 118.4, 68.3, 41.3, 34.5, 29.5. MS (HR-ESI) for C₂₀H₁₈N₂O₂S

[(M+Na)⁺], calcd: m/z 373.0987, found: m/z 373.0995.

4.1.5.1. N-(5-Benzylthiazol-2-yl)triﬂuoroacetamide (4a). White

solid; R_f0.41 (DCM); yield 56%. ¹H NMR (400 MHz, CDCl₃): d 13.77

(br s, 1H), 7.18–7.31 (m, 5H), 7.11 (s, 1H), 4.09 (s, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 167.2, 161.2, 137.8, 132.3, 129.2, 128.6, 127.5,

124.6, 115.4, 33.6. MS (HR-ESI) for C₁₂H₉F₃N₂OS [(M+Na)⁺], calcd:

m/z 309.0285, found: m/z 309.0278.

4.1.7. Synthesis of compound 14b and 16a

4.1.5.2. N-[5-(Naphthalen-1-ylmethyl)thiazol-2-yl]triﬂuoroacet-

amide (9a). White solid; R_f0.55 (DCM); yield 93%. ¹H NMR

(400 MHz, CDCl₃): d 13.86 (br s, 1H), 7.81–8.03 (m, 3H), 7.42–

7.48 (m, 4H), 7.11 (s, 1H), 4.51, (s, 2H). ¹³C NMR (100 MHz, CDCl₃):

d 166.8, 161.5, 134.2, 133.6, 132.1, 131.4, 129.2, 128.6, 127.2,

126.7, 126.2, 125.7, 124.8, 123.3, 115.4, 30.9. MS (HR-ESI) for C_16-

H₁₁F₃N₂OS [(M+Na)⁺], calcd: m/z 359.0442, found: m/z 359.0440.

To an ice-cooled mixture of NaH (40 mg, 60% in mineral oil,

1.6 mmol) in THF (10 mL) was added drop wise a solution of

compound 4f (0.25 g, 0.76 mmol) in THF (5 mL). The mixture

was stirred at room temperature for 20 min, again cooled to

0 °C, and methyl iodide (120 lL, 1.9 mmol) was added drop wise.

The mixture was then stirred at room temperature for 2 h. Water

(5 mL) was added to quench the reaction and the mixture was

extracted with DCM. The combined organic layers were dried

over anhydrous Na₂SO₄, evaporated, and the residue was sepa-

rated/puriﬁed by silica gel chromatography to afford products

14b and 16a.

4.1.6. General procedure for the synthesis of compounds 4g, 5a–

5c, and 5g

To a mixture of compound 3a (1 equiv), alicyclic carboxylic acid

(1.3 equiv), DMAP (0.45 equiv), triethylamine (1.8 equiv) in DCM/

DMF (ꢀ2 mL 3:1, v:v) was added EDAC (1.8 equiv) at room temper-

ature. The reaction mixture was stirred for 2 h, diluted with EtOAc,

and washed with brine, aqueous HCl (0.2 N), and aqueous sodium

bicarbonate solution. The organic phase was dried over anhydrous

Na₂SO₄and concentrated in vacuo. The residue was puriﬁed by sil-

ica gel column chromatography.

4.1.7.1. N-(5-Benzylthiazol-2-yl)-3-cyclohexyl-N-methylpropan-

amide (14b). White solid; R_f0.69 (hexane/EtOAc, 7:3); yield

38%. ¹H NMR (400 MHz, CDCl₃): d 7.21–7.34 (m, 6H), 4.11 (s, 2H),

3.72 (s, 3H), 2.63 (m, 2H), 1.56–1.83 (m, 7H), 1.11–1.39 (m, 4H),

0.91–1.04 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 172.6, 159.5,

139.9, 134.0, 133.9, 128.8. 128.6, 126.7, 37.3, 34.5, 33.2, 33.1,

32.3, 32.0, 26.6, 26.3. MS (HR-ESI) for C₂₀H₂₆N₂OS [(M+H)⁺], calcd:

m/z 343.1844, found: m/z 343.1830.

4.1.6.1. (E)-N-(5-Benzylthiazol-2-yl)-3-cyclohexylacrylamide (4g).

White solid; R_f0.69 (DCM/MeOH, 97:3); yield 77%. ¹H NMR

(400 MHz, CDCl₃): d 11.92 (br s, 1H), 7.22–7.33 (m, 5H), 7.11 (s,

1H), 7.01 (dd, J = 15.5 Hz, J = 6.4 Hz, 1H), 6.03 (d, J = 15.2 Hz, 1H),

4.1.7.2. (E)-N-(5-Benzyl-3-methylthiazol-2(3H)-ylidene)-3-cyclo-

hexylpropanamide (16a). White solid; R_f0.49 (hexane/EtOAc,

7:3); yield 32%. ¹H NMR (400 MHz, CDCl₃): d 7.21–7.43 (m,

5H), 6.53 (s, 1H), 3.89 (s, 2H), 3.62 (s, 3H), 2.51 (m, 2H), 1.62–

1.83 (m, 7H), 1.09–1.34 (m, 4H), 0.81–1.0 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 183.3, 166.9, 138.1, 129.0, 128.8, 127.2,

125.7, 122.6, 37.6, 37.5, 35.4, 33.9, 33.5, 33.4, 26.8, 26.5. MS

(HR-ESI) for C₂₀H₂₆N₂S [(M+H)⁺], calcd: m/z 343.1844, found:

m/z 343.1827.

4.13 (s, 2H), 2.23 (m, 1H), 1.71–1.94 (m, 5H), 1.01–1.41 (m, 5H). ¹³

C

NMR (100 MHz, CDCl₃): d 163.9, 154.0, 139.3, 133.5, 128.9, 128.7,

127.0, 119.5, 40.8, 33.2, 31.8, 26.1, 25.9. MS (HR-ESI) for C₁₉H_22-

N₂OS [(M+Na)⁺], calcd: m/z 349.1351, found: m/z 349.1356.

4.1.6.2. N-(5-Benzylthiazol-2-yl)tetrahydro-2H-thiopyran-4-car-

boxamide (5a). White solid; R_f0.55 (DCM/MeOH, 99:1); yield

39%. ¹H NMR (400 MHz, CDCl₃): d 12.31 (s, 1H), 7.32 (m, 2H),

546

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

4.1.8. General procedure for the synthesis of compounds 5d–5f

and 16b–16d

(HMM)³⁴at 37 °C in 95% air/5% CO₂. The Cryptococcus strain used

was the wild-type MAT serotype A strain H99 (kindly provided

a

A mixture of compound 3a (1 equiv), acid chloride (1 equiv),

and DMAP (1.2 equiv) in DCM (ꢀ2 mL) was stirred for 2 h at room

temperature. The solvent was evaporated and the residue was

puriﬁed by silica gel column chromatography.

by Tamara Doering). Cryptococcus yeasts were cultured in YPD

medium at 37 °C for routine maintenance or in HEPES-buffered

RPMI for growth in microtiter plates for dose response measure-

ments. For determination of the concentration of drug that inhibits

50% fungal growth (MIC₅₀), Histoplasma or Cryptococcus yeasts

were cultured in 96-well microtiter plates with a two-fold dilution

4.1.8.1. N-(5-Benzylthiazol-2-yl)pyrrolidine-1-carboxamide (5d).

White solid; R_f0.51 (EtOAc/hexanes, 1:1); yield 5%. ¹H NMR

(400 MHz, CDCl₃): d 8.03 (br s, 1H), 7.21–7.39 (m, 4H), 7.01 (s, 1H),

4.11 (s, 2H), 3.48 (s, 4H), 2.03 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): d

159.9, 152.1, 139.8, 133.7, 131.31, 128.8, 128.6, 126.8, 46.0, 33.2,

29.9. MS (HR-ESI) for C₁₅H₁₇N₃OS [(M+Na)⁺], calcd: m/z 310.0990,

found: m/z 310.0991.

series of each compound from 40 lM to 0.078 lM in 100 lL of

their respective growth medium. Wells were inoculated with

2 Â 10⁵Histoplasma yeasts or 2 Â 10²Cryptococcus yeasts (deter-

mined by hemocytometer counts) and plates were agitated twice

daily for improved aeration. Yeast growth was monitored by absor-

bance at 595 nm over 5 days (Histoplasma) or 4 days (Cryptococcus)

using a Synergy2 plate reader (BioTek). The turbidity in each well

was normalized to control wells lacking the antifungal compound

but with an equivalent amount of DMSO solvent (the 40 lM com-

4.1.8.2. N-(5-Benzylthiazol-2-yl)piperidine-1-carboxamide (5e).

White solid; R_f0.49 (EtOAc/hexanes, 1:1); yield 8%. ¹H NMR

(400 MHz, CDCl₃): d 7.21–7.33 (m, 5H), 7.02 (s, 1H), 4.04 (s, 2H),

3.41 (m, 4H), 1.47–1.68 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): d

161.7, 153.1, 139.7, 133.3, 128.8, 128.6, 126.8, 45.3, 33.2, 29.9,

25.7, 24.4. MS (HR-ESI) for C₁₆H₁₉N₃OS [(M+H)⁺], calcd: m/z

302.1327, found: m/z 302.1326.

pound dilution contained 1% DMSO). Relative turbidity measure-

ments at 4 days (Histoplasma) or 3 days (Cryptococcus) were used

for linear regression analysis and MIC₅₀determination. The mini-

mal inhibitory concentration preventing visible growth of fungi

(MIC) was determined by inspection of plates and visual assess-

ment of growth or no-growth. Compounds with an MIC₅₀

<3.5 lM in Histoplasma yeasts were also evaluated in Cryptococcus

yeasts. All compounds with an initial MIC₅₀<4.5

ated in triplicate.

lM were evalu-

4.1.8.3. N-(5-Benzylthiazol-2-yl)morpholine-4-carboxamide (5f).

White solid; R_f0.54 (DCM/MeOH, 19:1); yield 7%. ¹H NMR

(400 MHz, CDCl₃): d 9.51 (br s, 1H), 7.32 (m, 5H), 6.93 (s, 1H),

4.03 (s, 2H), 3.69 (m, 4H), 3.54 (m, 4H). ¹³C NMR (100 MHz, CDCl₃):

d 162.8, 155.6, 140.9, 133.7, 132.8, 130.2, 130.0, 128.3, 68.0, 45.69,

34.5, 31.3. MS (HR-ESI) for C₁₅H₁₇N₃O₂S [(M+H)⁺], calcd: m/z

304.1120, found: m/z 304.1127.

4.2.2. Evaluation of mammalian-cell toxicity

Cytotoxicity was evaluated using the human hepatocyte cell

line HepG2 (ATCC HB-8065) for selected compounds with an

MIC₅₀61.6 lM for Histoplasma yeasts. For mammalian cell cul-

ture, cells were maintained at 37 °C under 5% CO₂/95% air in

Minimum Essential Medium (MEM) supplemented with 10% fetal

4.1.8.4. N-[5-Benzyl-3-(pyrrolidine-1-carbonyl)thiazol-2(3H)-yli-

dene]pyrrolidine-1-carboxamide (16b). White solid; R_f0.72

(EtOAc/hexanes, 1:1); yield 25%. ¹H NMR (400 MHz, CDCl₃): d

7.21–7.43 (m, 5H), 6.61 (s, 1H), 3.93 (s, 2H), 3.41–3.69 (m, 8H),

1.87–2.01 (m, 8H). ¹³C NMR (100 MHz, CDCl₃): d 164.0, 160.7,

150.4, 137.7, 129.0, 128.9, 127.1, 124.9, 117.9, 47.7, 46.6, 45.5,

34.2, 25.3, 24.9. MS (HR-ESI) for C₂₀H₂₄N₄O₂S [(M+Na)⁺], calcd:

m/z 407.1518, found: m/z 407.1587.

bovine serum (FBS) and 2 mM

L-glutamine. Mammalian cells

were seeded into wells of a 96-well microtiter plate at 1 Â 10⁴

cells per well and allowed to adhere overnight. Antifungal com-

pounds were subsequently added to cells in a concentration

range from 80 lM to 0.3 lM. After 72 h, HepG2 cells were quan-

tiﬁed by measuring cell mass by crystal violet staining.³⁵Brieﬂy,

the growth medium was removed and cells washed once with

phosphate-buffered saline (PBS). Cells were ﬁxed in 3% parafor-

maldehyde, and stained with 0.1% crystal violet. Residual stain

was removed by washing cells repeatedly with water and the

retained crystal violet was solubilized in 10% acetic acid for

20 min with agitation. The retained dye was quantiﬁed by absor-

bance at 590 nm and normalized to untreated samples. Assays

were performed on three replicates. Results were compared to

control wells that lacked aminothiazole but contained an equiv-

alent amount of DMSO as mammalian cell growth was decreased

at solvent concentrations above 2%.

4.1.8.5. N-[5-Benzyl-3-(piperidine-1-carbonyl)thiazol-2(3H)-yli-

dene]piperidine-1-carboxamide (16c). White solid; R_f0.68

(EtOAc/hexanes, 1:1); yield 27%. ¹H NMR (400 MHz, CDCl₃): d

7.21–7.34 (m, 5H), 6.51 (s, 1H), 3.83 (s, 2H), 3.51–3.73 (m, 6H),

3.18 (m, 2H), 1.41–1.83 (m, 12H). ¹³C NMR (100 MHz, CDCl₃): d

166.3, 161.0, 150.9, 137.7, 128.9, 128.8, 127.1, 125.1, 118.2, 45.6,

43.8, 34.2, 26.4, 26.0, 24.9, 24.2. MS (HR-ESI) for C₂₂H₂₈N₄O₂S

[(M+Na)⁺], calcd: m/z 435.1831, found: m/z 435.1821.

4.1.8.6. N-(5-Benzyl-3-(morpholine-4-carbonyl)thiazol-2(3H)-yli-

dene)morpholine-4-carboxamide (16d). White solid; R_f0.64

(DCM/MeOH, 19:1) yield 23%. ¹H NMR (400 MHz, CDCl₃): d 7.21–

7.34 (m, 5H), 6.56 (s, 1H), 3.81 (s, 2H), 3.49–3.77 (m, 16H). ¹³C

NMR (100 MHz, CDCl₃): d 166.0, 161.1, 150.8, 137.4, 129.0, 128.9,

127.3, 125.8, 118.2, 67.0, 66.5, 45.1, 43.3, 34.2. MS (HR-ESI) for C₂₀

H₂₄N₄O₄S [(M+Na)⁺], calcd: m/z 439.1416, found: m/z 439.1413.

Acknowledgements

We thank The Ohio State University (OSU) Medical Center Clin-

ical Microbiology Laboratory and Tamara Doering for providing

fungal strains for testing. The project described was supported by

Award Number Grant 8UL1TR000090-05 from the National Center

for Advancing Translational Sciences and, in part, NIH (NIAID)

Grant R21AI109437. The content is solely the responsibility of

the authors and does not necessarily represent the ofﬁcial views

of the National Center For Advancing Translational Sciences or

the National Institutes of Health. This work was supported by

funds provided by the OSU Public Health Preparedness for Infec-

tious Diseases (PHPID) program (phpid.osu.edu) and by the OSU

College of Pharmacy.

4.2. Biology

4.2.1. Fungal strains and culture

The Histoplasma capsulatum strain used in this study was the

wild-type strain G217B (ATCC 26032). Histoplasma cells were

maintained as yeasts by growth in Histoplasma-macrophage media

A. Khalil et al. / Bioorg. Med. Chem. 23 (2015) 532–547

547

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Article Doi

Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans

DOI: 10.1016/j.bmc.2014.12.006

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