Synthesis, characterization, and antimicrobial evaluation of novel naphthalene-based 1,2,4-triazoles

Article abstract of DOI:10.1007/s00044-011-9833-8

In order to search for new bioactive molecules with significant antimicrobial action, a series of 1,2,4-triazole and naphthalene analogs bearing structurally diverse substituents, N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4- triazol-4-yl)(aryl)amides 3a-l were synthesized in good yield by a multi-step synthetic procedure. Their antimicrobial activity was screened against various Gram-positive and Gram-negative bacteria and fungi. Compounds 3a, 3f, 3g, 3j, and 3k exerted strong inhibition of the investigated bacterial and fungal strains compared to control antibiotic ampicillin and antifungal griseofulvin. On the basis of statistical analysis, it is observed that the compounds give significant co-relation. All the synthesized compounds have been characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral data. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9833-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2981–2989
DOI 10.1007/s00044-011-9833-8
ORIGINAL RESEARCH
Synthesis, characterization, and antimicrobial evaluation of novel
naphthalene-based 1,2,4-triazoles
•
N. C. Desai P. N. Shihora K. M. Rajpara V. V. Joshi
•
•
•
•
H. V. Vaghani H. M. Satodiya A. M. Dodiya
•
Received: 27 August 2011 / Accepted: 20 October 2011 / Published online: 3 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In order to search for new bioactive molecules
with significant antimicrobial action, a series of 1,2,4-tri-
azole and naphthalene analogs bearing structurally diverse
substituents, N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-
triazol-4-yl)(aryl)amides 3a–l were synthesized in good
yield by a multi-step synthetic procedure. Their antimi-
crobial activity was screened against various Gram-posi-
tive and Gram-negative bacteria and fungi. Compounds 3a,
3f, 3g, 3j, and 3k exerted strong inhibition of the investi-
gated bacterial and fungal strains compared to control
antibiotic ampicillin and antifungal griseofulvin. On the
basis of statistical analysis, it is observed that the com-
pounds give significant co-relation. All the synthesized
improved potential for treatment of microbial infections
and with decreased probability of developing drug resis-
tance. Heterocyclic compounds are commonly used as
scaffolds on which pharmacophores are arranged to pro-
vide potent and selective drugs (Krchnak and Holladay,
2002; Nefzi et al., 1997; Terrett et al., 1995). This is
especially true for five-membered ring heterocyclic com-
pounds, which serve as core components of a large number
of substances that possess a wide range of interesting
biological activities (Desai et al., 2010a, b, 2011a, b).
1,2,4-Triazole is a versatile lead molecule for develop-
ing potential bioactive agents. Derivatives of this particular
lead structure containing ring systems have been incorpo-
rated to yield a wide variety of therapeutically interesting
activities including antibacterial (Holla et al., 1994), anti-
inflammatory (Sahin et al., 2001), CNS depressant (Parmar
et al., 1972), anti-tubercular (Dabak et al., 2003), anti-HIV
(Alvarez et al., 1994), and anti-proliferative (Manfredini
et al., 2000). 1,2,4-Triazole system is a structural element
of many drugs that have anti-mycotic activity such as
fluconazole, intraconazole, and voriconazole (Haber,
2001). Also, there are other known drugs containing 1,2,4-
triazole group, e.g., triazolam, rizatriptan, nefazodone,
vorozole, ribavirin, letrozole, uniconazole, alprazolam, and
etizolam. Anastrozole is an aromatase inhibitor, which
interrupts synthesis of estrogen in the body (Wellington
and Faulds 2002). 1-Acyl-1H-[1,2,4]triazole-3,5-diamine
analogs are found to be potent as anticancer and cyclin-
dependent kinase inhibitors (Lin et al., 2005). Literature
described triazole as an antiplatelet agent (Cunha et al.,
2003), selective GSK-3 inhibitor (Olesen et al., 2003),
dopamine D2-receptor ligand related to schizophrenia
(Menegatti et al., 2003), ghrelin receptor (Demange et al.,
2007), anticonvulsant (Kelley et al., 1995), selective
adenosine A2A receptor antagonist (Peng et al., 2004),
1
compounds have been characterized by IR, H NMR, 13C
NMR, and mass spectral data.
Keywords 1,2,4-Triazole ꢀ Naphthalene ꢀ
Antibacterial activity ꢀ Antifungal activity ꢀ MIC
Introduction
In the last few decades, though significant progress has
been made in treatment and control strategies of microbial
infections by introducing new diagnostic, monitoring tools
and combination therapy, it still continues to be a severe
problem. Thus, we embarked in our programme which is
aimed at development of novel drug molecules with
N. C. Desai (&) ꢀ P. N. Shihora ꢀ K. M. Rajpara ꢀ
V. V. Joshi ꢀ H. V. Vaghani ꢀ H. M. Satodiya ꢀ A. M. Dodiya
Division of Medicinal Chemistry, Department of Chemistry,
Mahatma Gandhi Campus, Bhavnagar University, Bhavnagar
364 002, India
e-mail: dnisheeth@rediffmail.com
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Med Chem Res (2012) 21:2981–2989
b-lactamase inhibitor (Micetich et al., 1987), inhibitor of
hormone sensitive lipase (Ebdrup et al., 2004), and
GABAA receptor agonist (Russell et al., 2005).
yield by reacting 1-naphthohydrazide (1) with carbon
disulfide and potassium hydroxide. Compound 2 on cycli-
zation with N-aminoarylcarboxamides afforded N-(3-mer-
capto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)arylamides
(3a–l).
Naphthalene derivatives have been identified as a new
range of potent antimicrobial, effective against wide range
of human pathogens. Substituted naphthalene showed a
variety of biological activities such as antihypotensive
(Tandon et al., 2004), enhanced affinity for human
5-HT1DB (h5-HT1B) serotonin-receptor (Ismaiel et al.,
1997), antagonists of human CCR8 (Jenkins et al., 2007),
antitumor, DNA photocleaving (Li et al., 2005), antima-
larial (Harpstrite et al., 2008), non-nucleoside HIV-1
reverse transcriptase inhibitor (Zhan et al., 2009), cyto-
toxicity, and anti-tubulin (Medarde et al., 2004). Several
naphthalene containing drugs are available, such as nafa-
cillin, naftifine, tolnaftate, terbinafine, etc. Naftifine is an
antifungal drug for the topical treatment of tinea pedis,
tinea cruris and tinea corporis (fungal infections) (Wilson,
2004). The synthesis of new compounds is of vital
importance due to increasing drug resistance. Moreover, it
is important to obtain therapeutically active compounds
having less toxic effects.
Characterization
Characterization of the newly synthesized compounds of
this series was accomplished by IR, NMR, mass spectra,
and elemental analysis.
IR spectrum of title compound 3g (molecular formula
C19H13ClN4OS, m.w. 380.85 gm/mol) has given stretching
vibration at 3328 cm-1 over the range, showing medium
intensity absorption peak corresponding to secondary
amine in amide linkage. Absorption bands at 3079 and
3052 cm-1 over the ranges are due to Ar–H stretching
vibrations. Weak intensity absorption band at 2565 cm-1 is
due to stretching vibration of S–H. Strong intensity
absorption band at 1716 cm-1 is due to stretching vibration
of C=O of amide linkage, while the weak intensity
absorption band at 1618 cm-1 corresponds to a C=N
CH
3
NC
CH
3
N
N
N
CN
CH
CH
N
3
3
Naftifine
H C
3
Anastrozole
Motivated by the aforementioned findings and in con-
tinuation of our ongoing research program in the field of
1,2,4-triazole and naphthalene derivatives as antimicrobial
agents, we have developed an efficient procedure for the
synthesis of a new class of heterocyclic molecules in which
both moieties are present. The structures of synthesized
stretching vibration and medium intensity absorption band
is observed due to C=C stretching vibration at 1552 and
1445 cm-1. Strong intensity absorption band at 789 cm-1
is attributed to the stretching vibration of C–Cl bond.
In 1H NMR spectra, it has been observed from the
chemical structure of compound 3g that pair of carbons, e.g.,
C-8 and C-9 are attached to chemically equivalent protons,
which appeared as doublet at a d = 7.39 ppm. The SH
protons on C-12 appeared as a singlet at d = 3.38 ppm due
to the influence of attachment with triazole ring. Protons
attached to carbons C-1, C-2, C-3, C-7, and C-10 in naph-
thalene ring appeared as a multiplet at d = 7.19–7.63 ppm,
respectively. Proton of the secondary amine appeared as a
singlet at d = 9.87 ppm. Protons attached to C-15, C-16,
C-17, and C-19 of chlorophenyl ring appeared as a multiplet
at d = 7.16–7.91 ppm, respectively.
1
compounds are assigned on the basis of IR, H NMR, 13C
NMR, and mass spectral data. These compounds are
evaluated for their antimicrobial screening on different
strains of bacteria and fungi.
Results and discussion
Chemistry
The synthetic strategies adopted to obtain the target com-
pounds are shown in Scheme 1. Present scaffold 3 is a part
of synthesis of new chemical entities in the form of anti-
microbial agents. Scaffold 2 is prepared in an excellent
Looking at 13C NMR, chemical shifts of the final
compound 3g vary from d = 164.4–124.6 ppm. Carbon
nucleus under the influence of a strong electronegative
environment appeared downfield, e.g., C-13, i.e., carbonyl
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Med Chem Res (2012) 21:2981–2989
2983
Carbons of chloro phenyl ring C-14, C-15, C-16, C-17, and
C-19 gave a chemical shift between d = 126.2–133.2 ppm,
respectively. Carbon enumeration of compound 3g is
described in Fig. 1.
S
O
NH
O
NH
S- K+
NH
NH2
CS2, KOH
Ethanol,
Antimicrobial screening
Stirring, 3h
2
o
1
30-35 C
Many of the newly synthesized compounds are found to
exhibit good to excellent antimicrobial activity. From
antimicrobial activity data (Table 1), it is observed that
compounds 3a (–C6H5), 3f (2-Cl–C6H4), 3 g (3-Cl–C6H4),
3j (4-NO2–C6H4), and 3k (8-NO2–C10H7) are most active.
For antibacterial activity, compounds 3b (2-CH3–C6H4), 3c
(2-OCH3–C6H4), 3h (3-NO2–C6H4), and 3l (–C10H7–
OCH2) possess good activity against E. coli, while com-
pounds 3f and 3j possess very good activity against E. coli.
Compound 3f contains chloro substitution at 2-position and
compound 3j contains 4-nitro substitution. Replacement of
hydrogen by 3-chloro substituent in 3a leads to 3g,
enhances the activity against E. coli. Compounds 3b
(2-CH3–C6H4), 3f (2-Cl–C6H4), 3h (3-NO2–C6H4), 3i
(4-OH–C6H4), and 3k (8-NO2–C10H7) possess good
activity against P. aeruginosa. When there is no substitu-
tion on phenyl ring in 3a it possesses very good activity,
while replacement with 4-nitro group in compound 3j,
enhances the activity against P. aeruginosa. Compounds 3c
(2-OCH3–C6H4), 3d (C6H5–CH2), 3g (3-Cl–C6H4), 3j
(4-NO2–C6H4), 3k (8-NO2–C10H7), and 3l (C10H7–OCH2)
possess good activity against S. aureus, while compounds
3 h (3-NO2–C6H4) and 3i (4-OH–C6H4) possess very good
activity against S. aureus. Compounds 3b and 3g possess
good activity against S. pyogenes, compound 3b contains
methyl group and compound 3g contains chloro group as
substitution. For antifungal activity, compounds 3b
(2-CH3–C6H4), 3c (2-OCH3–C6H4), 3e (2-OH–C6H4), 3h
(3-NO2–C6H4), 3i (4-OH–C6H4), and 3l (–C10H7–OCH2)
displayed good activity against C. albicans. When we
replace the substitution with 8-NO2–C10H7 in compound
3k, it showed very good activity against C. albicans. Fur-
thermore, replacement with chloro group at 2 and 3-posi-
tion, i.e., 3f and 3g, respectively, and nitro group at
4-position in 3j, the activity is enhanced and it shows
excellent activity against C. albicans. Compounds 3f
(2-Cl–C6H4) and 3k (8-NO2–C10H7) possess good activity
against A. niger, at the same time if we replace it by groups
like 3-chloro and 4-nitro in 3g and 3j, it possesses very
good activity against A. niger. Compounds 3b (2-CH3–
C6H4) and 3h (3-NO2–C6H4) possess good activity against
A. clavatus. It is our observation that replacement of chloro
group at third position in 3g, nitro group at fourth position
in 3j and nitro group at eighth position in 3k raises activity
and it possesses excellent activity against A. clavatus. The
enhancement of activity of these compounds is due to the
R-CONHNH2
Reflux, 8 h
Ethanol
SH
O
N
N
R
N
NH
3a-l
Where, R = Different substituents
Scheme 1 Synthetic route of the final compounds (3a–l)
carbon, which is present in amide linkage directly linked to
nitrogen, has a chemical shift value of d = 164.4 ppm.
Carbons present in triazole nucleus C-11 and C-12 on both
sides are directly attached to nitrogen atom. So, carbon
C-11 gave a chemical shift at d = 147.1 ppm and C-12
gave a chemical shift at d = 151.6 ppm. Carbon C-12 was
more downfield than C-11 due to direct attachment to thiol
group. Carbon C-18 appeared at d = 134.6 ppm due to the
influence of chloro group. Carbons are present in naph-
thalene ring C-1, C-2, C-3, C-4, C-5, and C-6 gave a
chemical shift between d = 124.6–134.9 ppm, respec-
tively. Carbons of the phenyl ring C-8 and C-9 which
are equivalent carbons gave a chemical shift at d =
126.00 ppm, while carbons C-7 and C-10 which are
also equivalent gave a chemical shift at d = 127.5 ppm.
Cl
19
SH
18
O
12
14
13
NH
N
17
N
11
N
15
16
10
6
3
5
4
1
2
9
8
7
Fig. 1 Carbon enumeration of the final compound-3g
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Table 1 Results of antibacterial and antifungal screening of compounds 3a–l
S. –R
no.
Minimum inhibitory concentration (MIC) in lg/ml SD
Minimum inhibitory concentration (MIC) in
lg/ml SD
E. coli
MTCC 443
P. aeruginosa
MTCC 1688
S. aureus
MTCC 96
S. pyogenes
MTCC 442
C. albicans
MTCC 227
A. niger
MTCC 282
A. clavatus
MTCC 1323
3a –C6H5
500 4.93
100 3.05
50 2.64*** 500 3.78*
100 3.46* 500 3.21
1000 2.64*
100 4.04**
1000 3.78** 1000 3.05
200 3.05*** 500 3.51
1000 3.21
100 4.05*
3b –2–CH3–
C6H4
3c –2–OCH3–
C6H4
100 3.78*** 250 3.21*
250 2.08*** 500 2.51
200 3*
200 4.50*** 500 4.35
3d –C6H5–CH2 500 4.50
500 3.51
1000 1**
250 2.08
500 4.04
200 2.64*
500 2.51*
1000 4.50
500 3.21
500 4.21
500 2.08
500 4.16**
200 3.78***
3e –2–OH–
C6H4
1000 1*
50 1***
25 1***
100 2.64
250 4.58
50 4.05
3f –2–Cl–
C6H4
100 3.60** 500 3.78**
500 3.78
100 3.51***
500 3.78
500 4.50
500 3.05
250 2.08*
500 3.51**
100 2.06
50 1***
50 2.05**
200 4.04
500 4.93
50 3.21*
100 2.30**
500 2.51*
100 3.05*
50 2.64**
250 3.78
50 3.51*
100 3.05**
500 4.58
50 3.21***
50 2.46*
500 4**
3g –3–Cl–
C6H4
250 4.72
100 3.05
100 2.08*
25 1**
250 3.05*
100 4.16
100 4.04**
250 4.50
250 2.64
250 3.21*
250 1.52
3h –3–NO2–
C6H4
200
4
3i –4–OH–
C6H4
500 3.78
50 3.05***
100 3.05*
500 2.64
–
3j –4–NO2–
C6H4
3k –8–NO2–
C10H7
200 3.21*** 100 3**
3l –C10H7–
OCH2
100 3.05**
100 2.05
250 3.78
100 1.0
Ampicillin
–
–
Griseofulvin
500 0.58
100
1
100 1.15
SD standard deviation, *** P \ 0.001 extremely significant , ** P \ 0.01 moderately significant, * P \ 0.05 significant
All values are presented as mean of 10 experiments (n = 6). All significant differences are considered from control value 0.00
presence of chloro and nitro groups in title compounds. We
have discussed and compared antibacterial and antifungal
activities based on standard drugs ampicillin and griseo-
fulvin, respectively.
Escherichia coli, Staphylococcus aureus, Pseudomonas
aeruginosa, and Streptococcus pyogenes at different con-
centrations of 1000, 500, 200, 100, 50, and 25 lg/ml as
shown in Table 1. The compounds found to be active in
primary screening are similarly diluted to obtain 100, 50,
and 25 lg/ml concentrations. Ten microgram per milliliter
suspensions are further inoculated on appropriate media
and growth is noted after 24 and 48 h. The lowest con-
centration, which shows no growth after spot subculture is
considered as MIC for each drug. The highest dilution
showing at least 99% inhibition is taken as MIC. The test
mixture should contain 108 cells/ml. Standard drug used in
this study is ‘ampicillin’ for evaluating antibacterial
activity which shows 100, 100, 250, and 100 lg/ml MIC
against E. coli, P. aeruginosa, S. aureus, and S. pyogenes,
respectively. For bacterial growth, in the present protocol,
we have used Muller Hinton broth at 37°C in aerobic
condition for 24–48 h.
Antibacterial assay
The newly synthesized compounds are screened for their
antibacterial activity against Gram positive bacteria
(Staphylococcus aureus (MTCC-96), Streptococcus pyog-
enes (MTCC-442)), and Gram-negative (Escherichia coli
(MTCC-443), Pseudomonas aeruginosa (MTCC-1688)).
Antibacterial activity is carried out by serial broth dilution
method (Desai et al., 2010a, b, 2011a, b; Al-Bayati and
Al-Mola, 2008). Standard strains which are used for anti-
microbial activity are procured by The Institute of Micro-
bial Technology, Chandigarh. Compounds (3a–l) are
screened for their antibacterial activity in six sets against
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Med Chem Res (2012) 21:2981–2989
Antifungal assay
2985
conventional method, compounds are synthesized by using
Random synthesizer. Buchi Rotavapor is used for
distillation.
The same compounds are tested for antifungal activity in
six sets against Candida albicans, Aspergillus niger, and
Aspergillus clavatus at various concentrations of 1000,
500, 200, and 100 lg/ml as shown in Table 1. Results are
recorded in the form of primary and secondary screening.
Synthesized compounds are diluted to 1000 lg/ml con-
centration, as a stock solution. Synthesized compounds
which are found to be active in this primary screening are
further tested in second set of dilution against all micro-
organisms. The lowest concentration, which shows no
growth after spot subculture is considered as MIC for each
drug. The highest dilution showing at least 99% inhibition
is taken as MIC. Test mixture should contain 108 spores/ml
MIC. Griseofulvin is used as a standard drug for antifungal
activity, which shows 500, 200, 100 and 50 lg/ml MIC
against C. albicans, A. niger, and A. clavatus, respectively.
Results of antimicrobial evaluation of derivatives (3a–l)
are shown in Table 1. For fungal growth, in the present
protocol, we have used Sabourauds dextrose broth at 22°C
in aerobic condition for 72 h.
Experimental
Preparation of 1-naphthohydrazide (1)
Compound 1-naphthohydrazide (1) is prepared according
to literature method (Mathew et al. 2006).
Preparation of potassium 2-(2-
naphthoyl)hydrazinecarbodithioate (2)
To a solution of KOH in alcohol (99.9%) (0.1 mol),
1-naphthohydrazide 1 (0.1 mol) and carbon disulfide
(0.1 mol) are added drop wise with constant stirring and
the mixture is stirred for 3 h. Resulting white solid is
separated out, filtered, and washed with petroleum ether.
General procedure for preparation of 3-mercapto-5-
(naphthalene-1-yl)-N-aryl-4H-1,2,4-triazole-4-
carboxamides (3a–l)
Statistical analysis
A mixture of compound 2 (0.1 mol) and N-amino-aryl-
carboxamides (0.1 mol) in ethanol (95%) (25 ml) con-
taining is refluxed for 6 h. The solution is poured into cold
water and subsequent is acidified to pH 8 with hydrochloric
acid resulting in white precipitates. The solid product is
filtered, washed with water, and recrystallized from alcohol
(99.9%).
Standard deviation value is expressed in terms of SD. On
the basis of calculated value by using One-way ANOVA
method followed by independent two sample t test, it has
been observed that differences below 0.001 level are con-
sidered statistically significant. Compounds (3a–l) are
screened for their antibacterial and antifungal activities in
six sets (n) against bacteria and fungi used in the present
protocol.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-
yl)benzamide (3a)
Yield: 78%; m.p.: 156–158°C; IR (KBr, cm-1): 3335 (–NH
stretching, secondary amine), 3085, 3057 (C–H stretching,
aromatic ring), 2575 (–SH stretching, thiol), 1715 (C=O
stretching, amide), 1610, 1535, 1455 (C=N, C=C, aromatic
Materials and methods
Completion of reaction and purity of all compounds is
checked on aluminum coated TLC plates 60 F245
(E. Merck) using n-hexane: ethyl acetate (7.5:2.5 V/V) as
mobile phase and visualized under ultraviolet (UV) light or
iodine vapor. Melting points are determined on an electro
thermal melting point apparatus and are reported uncor-
rected. Elemental analysis (% C, H, N) is carried out by a
Perkin-Elmer 2400 CHN analyser. IR spectra of all com-
pounds have been recorded on a Perkin-Elmer FT-IR
spectrophotometer in KBr. 1H NMR and 13C NMR spectra
are recorded on Bruker (400 MHz) spectrometer using
DMSO-d6 as a solvent and TMS as an internal standard.
Mass spectra are obtained on Schimadzu LCMS 2010
spectrophotometer. Anhydrous reactions are carried out
in dried glassware in nitrogen atmosphere. In the
1
ring stretching); H NMR (400 MHz, DMSO-d6, d, ppm):
3.30 (s, 1H, –SH), 7.10–7.70 (m, 12H, Ar–H), 9.85 (s, 1H,
–CONH); 13C NMR (400 MHz, DMSO-d6, d, ppm): 124.4,
126.1, 126.5, 127.2, 127.6, 128.1, 128.5, 132.8, 133.7,
133.1, 134.7, 137.3, 147.1, 151.6, 164.3; LCMS (m/z): 348
(M?). Anal. Calcd. For C19H14N4OS C-65.87, H-4.07,
N-16.17; Found: C-65.74, H-4.02, N-16.21%.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
2-methylbenzamide (3b)
Yield: 74%; m.p.: 215–217°C; IR (KBr, cm-1): 3331 (–NH
stretching, secondary amine), 3087, 3054 (C–H stretching,
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Med Chem Res (2012) 21:2981–2989
aromatic ring), 2918 (C–H stretching, –CH3), 2570 (–SH
stretching, thiol), 1711 (C=O stretching, amide), 1618,
1542, 1448 (C=N, C=C, aromatic ring stretching), 1391
3071, 3047 (C–H stretching, aromatic ring), 2562 (–SH
stretching, thiol), 1710 (C=O stretching, amide), 1620,
1540, 1451 (C=N, C=C, aromatic ring stretching); 1H
NMR (400 MHz, DMSO-d6, d, ppm): 3.34 (s, 1H, -SH),
7.16–7.87 (m, 11H, Ar–H), 9.78 (s, 1H, –OH), 9.86 (s, 1H,
–CONH); 13C NMR (400 MHz, DMSO-d6, d, ppm): 117.5,
120.1, 121.2, 124.3, 126.2, 126.5, 127.2, 128.1, 128.6,
132.6, 133.8, 134.7, 137.3, 147.5, 151.3, 155.1, 164.4;
LCMS (m/z): 362 (M?). Anal. Calcd. For C19H14N4O2S:
C-62.97, H-3.89, N-15.46; Found: C-62.85, H-3.77,
N-15.58%.
1
(C–H bending, –CH3); H NMR (400 MHz, DMSO-d6, d,
ppm): 1.21 (s, 3H, –CH3), 3.32 (s, 1H, –SH), 7.15–7.79 (m,
11H, Ar–H), 9.84 (s, 1H, –CONH); 13C NMR (400 MHz,
DMSO-d6, d, ppm): 17.2, 124.2, 126, 126.2, 127.3, 128.2,
128.5, 130.5, 132.5, 132.6, 134.5, 134.6, 137.1, 137.5,
147.3, 151.6, 164.1; LCMS (m/z): 360 (M?). Anal. Calcd.
For C20H16N4OS: C-66.65, H-4.47, N-15.54; Found:
C-66.70, H-4.52, N-15.60%.
2-Chloro-N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-
triazol-4-yl)benzamide (3f)
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
2-methoxybenzamide (3c)
Yield: 74%; m.p.: 175–177°C; IR (KBr, cm-1): 3329 (–NH
stretching, secondary amine), 3075, 3041 (C–H stretching,
aromatic ring), 2571 (–SH stretching, thiol), 1712 (C=O
stretching, amide), 1612, 1547, 1440 (C=N, C=C, aromatic
ring stretching), 780 (C–Cl stretching, C–Cl); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 3.36 (s, 1H, –SH),
7.17–7.89 (m, 11H, Ar–H), 9.87 (s, 1H, –CONH); 13C
NMR (400 MHz, DMSO-d6, d, ppm): 124.2, 126.1, 126.3,
126.6, 127.5, 128.2, 129.2, 130.2, 132.1, 132.5, 134.5,
134.6, 134.4, 137.3, 147.2, 151.4, 164.5; LCMS (m/z): 380
(M?). Anal. Calcd. For C19H13ClN4OS: C-59.92, H-3.44,
N-14.71; Found: C-59.85, H-3.52, N-14.63%.
Yield: 73%; m.p.: 199–201°C; IR (KBr, cm-1): 3338 (–NH
stretching, secondary amine), 3082, 3062 (C–H stretching,
aromatic ring), 2943 (C–H stretching, –OCH3), 2565 (–SH
stretching, thiol), 1713 (C=O stretching, amide), 1610,
1544, 1452 (C=N, C=C, aromatic ring stretching), 1400
(C–H bending, –OCH3), 1207 (C–O–C stretching, –OCH3);
1H NMR (400 MHz, DMSO-d6, d, ppm): 3.30 (s, 1H,
–SH), 3.46 (s, 3H, –OCH3), 7.17–7.82 (m, 11H, Ar–H),
9.85 (s, 1H, –CONH); 13C NMR (400 MHz, DMSO-d6, d,
ppm): 55.8, 117.9, 119.4, 120.8, 124.7, 126.4, 126.6, 127.5,
128.2, 128.6, 132.4, 133.4, 134.7, 137.1, 147.2, 151.6,
157.4, 164.3; LCMS (m/z): 376 (M?). Anal. Calcd. For
C20H16N4O2S: C-63.81, H-4.28, N-14.88; Found: C-63.72,
H-4.36, N-14.77.
3-Chloro-N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-
triazol-4-yl)benzamide (3g)
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
2-phenylacetamide (3d)
Yield: 71%; m.p.: 186–188°C; IR (KBr, cm-1): 3328 (–NH
stretching, secondary amine), 3079, 3052 (C–H stretching,
aromatic ring), 2565 (–SH stretching, thiol), 1716 (C=O
stretching, amide), 1618, 1552, 1445 (C=N, C=C, aromatic
ring stretching), 789 (C–Cl stretching, C–Cl); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 3.38 (s, 1H, –SH),
7.16–7.91 (m, 11H, Ar–H), 9.87 (s, 1H, –CONH); 13C
NMR (400 MHz, DMSO-d6, d, ppm): 124.6, 125.2, 126,
126.2, 127.3, 127.5, 128.3, 130.1, 132.8, 133.2, 134.3,
134.7, 137.1, 134.9, 147.1, 151.6, 164.4; LCMS (m/z): 380
(M?). Anal. Calcd. For C19H13ClN4OS: C-59.92, H-3.44,
N-14.71; Found: C-59.85, H-3.52, N-14.75%.
Yield: 77%; m.p.: 186–188°C; IR (KBr, cm-1): 3329 (–NH
stretching, secondary amine), 3079, 3067 (C–H stretching,
aromatic ring), 2869 (C–H stretching, –CH2–), 2568 (–SH
stretching, thiol), 1712 (C=O stretching, amide), 1618,
1541, 1435 (C=N, C=C, aromatic ring stretching), 1456
(C–H bending, –CH2–); 1H NMR (400 MHz, DMSO-d6, d,
ppm): 3.30 (s, 1H, –SH), 3.90 (s, 2H, –CH2) 7.12–7.68 (m,
11H, Ar–H), 9.81 (s, 1H, –CONH); 13C NMR (400 MHz,
DMSO-d6, d, ppm): 37.8, 124.6, 126.1, 126.4, 127.2, 127.9,
128.5, 129.3, 129.5, 132.7, 134.7, 135.6, 137.3, 147.2,
151.4, 166.4; LCMS (m/z): 360 (M?). Anal. Calcd. For
C20H16N4OS: C-66.65, H-4.47, N-15.54; Found: C-66.53,
H-4.58, N-15.62%.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
3-nitrobenzamide (3h)
Yield: 69%; m.p.: 195–197°C; IR (KBr, cm-1): 3334 (–NH
stretching, secondary amine), 3083, 3052 (C–H stretching,
aromatic ring), 2567 (–SH stretching, thiol), 1712 (C=O
stretching, amide), 1605, 1557, 1440 (C=C, C=N, aromatic
ring stretching), 1485 (NO2 group, asymmetric stretching),
1355 (NO2 group, symmetric stretching); 1H NMR
2-Hydroxy-N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-
triazol-4-yl)benzamide (3e)
Yield: 70%; m.p.: 225–227°C; IR (KBr, cm-1): 3410 (O–H
stretching, –OH), 3334 (–NH stretching, secondary amine),
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Med Chem Res (2012) 21:2981–2989
2987
(400 MHz, DMSO-d6, d, ppm): 3.37 (s, 1H, –SH), 7.19–
8.15 (m, 11H, Ar–H), 9.89 (s, 1H, –CONH); 13C NMR
(400 MHz, DMSO-d6, d, ppm): 123.3, 124.1, 126.4, 126.6,
127.2, 127.4, 128.1, 129.4, 132.5, 133.6, 134.7, 135.1,
137.4, 147.2, 147.4, 151.2, 164.5; LCMS (m/z): 391 (M?).
Anal. Calcd. For C19H13N5O3S: C-58.30, H-3.35, N-17.89;
Found: C-58.22, H-3.42, N-17.91%.
13C NMR (400 MHz, DMSO-d6, d, ppm): 37.9, 123.1,
124.3, 126.3, 126.5, 127.1, 128.5, 128.7, 128.9, 132.4,
134.6, 137.3, 142.8, 145.6, 147.5, 151.6, 166.7; LCMS
(m/z): 441 (M?). Anal. Calcd. For C23H15N5O3S : C-62.58,
H-3.42, N-15.86; Found: C-62.52, H-3.38, N-15.79%.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
2-(naphthalen-2-yloxy)acetamide (3l)
4-Hydroxy-N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-
triazol-4-yl)benzamide (3i)
Yield: 75%; m.p.: 187–189°C; IR (KBr, cm-1): 3328 (–NH
stretching, secondary amine), 3078, 3047 (C–H stretching,
aromatic ring), 2890 (C–H stretching, –CH2–), 2564 (–SH
stretching, thiol), 1714 (C=O stretching, amide linkage),
1602, 1548, 1440 (C=N, C=C, aromatic ring stretching),
1459 (C–H bending, –CH2–), 1120 (C–O–C stretching,
Yield: 76%; m.p.: 211–213°C; IR (KBr, cm-1): 3405 (O–H
stretching, –OH), 3340 (–NH stretching, secondary amine),
3078, 3039 (C–H stretching, aromatic ring), 1716 (C=O
stretching, amide), 1613, 1551, 1442 (C=N, C=C, aromatic
ring stretching), 2567 (–SH stretching, thiol); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 3.36 (s, 1H, –SH),
7.16–7.89 (m, 11H, Ar–H), 9.78 (s, 1H, –OH), 9.86 (s, 1H,
–CONH); 13C NMR (400 MHz, DMSO-d6, d, ppm): 116.1,
124.5, 126.3, 126.5, 126.7, 127.1, 128.5, 128.9, 132.6,
134.7, 137.4, 147.3, 151.3, 160.9, 164.3; LCMS (m/z): 362
(M?). Anal. Calcd. For C19H14N4O2S: C-62.97, H-3.89,
N-15.46; Found: C-62.85, H-3.77, N-15.58%.
1
ether linkage); H NMR (400 MHz, DMSO-d6, d, ppm):
3.30 (s, 1H, –SH), 5.10 (s, 2H, –CH2), 6.67–7.78 (m, 14H,
Ar–H), 9.85 (s, 1H, –CONH); 13C NMR (400 MHz,
DMSO-d6, d, ppm): 62.7, 113.4, 118.3, 124.5, 124.8, 126.3,
126.4, 126.5, 126.7, 127.5, 127.8, 128.3, 132.6, 133.6,
133.8, 134.7, 137.2, 147.3, 151.7, 156.2, 167.6; LCMS
(m/z): 426 (M?). Anal. Calcd. For C24H18N4O2S: C-67.59,
H-4.25, N-13.14; Found: C-67.64, H-4.32, N-13.21%.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
4-nitrobenzamide (3j)
Conclusion
Yield: 73%; m.p.: 169–171°C; IR (KBr, cm-1): 3340 (–NH
stretching, secondary amine), 3082, 3043 (C–H stretching,
aromatic ring), 2571 (–SH stretching, thiol), 1717 (C=O
stretching, amide), 1617, 1542, 1450 (C=N, C=C, aromatic
ring stretching), 1472 (NO2 group, asymmetric stretching),
1350 (NO2 group, symmetric stretching); 1H NMR
(400 MHz, DMSO-d6, d, ppm): 3.38 (s, 1H, –SH),
7.18–8.18 (m, 11H, Ar–H), 9.88 (s, 1H, –CONH); 13C
NMR (400 MHz, DMSO-d6, d, ppm): 124, 124.4, 126.2,
126.5, 127.5, 128.4, 129.5, 132.7, 134.6, 137.5, 138.9,
147.4, 151.5, 152.1, 164.5; LCMS (m/z): 391 (M?). Anal.
Calcd. For C19H13N5O3S: C-58.30, H-3.35, N-17.89;
Found: C-58.42, H-3.32, N-17.94%.
In the present investigation, we have synthesized 1,2,4-
triazole and naphthalene containing derivatives as micro-
organism growth inhibitors. The antibacterial screening
data reveal that among the synthesized compounds
screened, 3a, 3f, 3g, 3h, 3i, and 3j showed significant
bacterial growth inhibition almost greater than that of the
standard drugs. As far as antifungal screening results are
concerned 3f, 3g, 3j, and 3k displayed significant activity.
Hence, it is concluded that there is an ample scope for
further study in developing these as good lead compounds,
which can be used in the bigger scenario such as drug
design or development of antimicrobial therapeutics.
Acknowledgments We would like to express our sincere gratitude to
the Department of Chemistry, Mahatma Gandhi Campus, Bhavnagar
University, Bhavnagar for providing research and library facilities.
N-(3-mercapto-5-(naphthalen-1-yl)-4H-1,2,4-triazol-4-yl)-
8-nitro-2-naphthamide (3k)
Yield: 69%; m.p.: 205–207°C; IR (KBr, cm-1): 3332 (–NH
stretching, secondary amine), 3080, 3038 (C–H stretching,
aromatic ring), 2874 (C–H stretching, –CH2–), 2570 (–SH
stretching, thiol), 1718 (C=O stretching, amide), 1611,
1551, 1444 (C=N, C=C, aromatic ring stretching), 1470
(NO2 group, asymmetric stretching), 1452 (C–H bending,
–CH2–), 1354 (NO2 group, symmetric stretching); 1H
NMR (400 MHz, DMSO-d6, d, ppm): 3.34 (s, 1H, –SH),
7.16-8.10 (m, 13H, Ar–H), 9.83 (s, 1H, –CONH);
References
Al-Bayati FA, Al-Mola HF (2008) Antibacterial and antifungal
activities of different parts of Tribulus terrestris L growing in
Iraq. J Zhenjiang 9:154–159. doi:10.1631/jzus.B0720251
Alvarez R, Velazquez S, San-Fe’lix A, Aquaro S, De Clercq E, Perno CF,
Karlsson A, Balzarini J, Camarasa MJ (1994) 1,2,3-Triazole-[2,
5-bis-o-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-30-spiro-500-
(400-amino-100,200-oxathiole200,200-dioxide)(TSAO) analogs: syn-
thesis and anti-HIV-1 activity. J Med Chem 37:4185–4194. doi:
10.1021/jm00050a015
123

2988
Med Chem Res (2012) 21:2981–2989
Cunha AC, Figueiredo JM, Tributino JL, Miranda AL, Castro HC,
Zingali RB, Fraga CA, De Souza MC, Ferreira VF, Barreiro EJ
(2003) Antiplatelet properties of novel N-substituted-phenyl-
1,2,3-triazole-4-acylhydrazone derivatives. Bioorg Med Chem
11:2051–2059. doi:10.1016/S0968-0896(03)00055-5
chains. Tetrahedron 61:8711–8717. doi:10.1016/j.tet.2005.06.
097
Lin R, Connolly PJ, Huang S, Wetter SK, Lu Y, Murray WV,
Emanuel SL, Gruninger AR, Ruggs CA (2005) 1-Acyl-1H-
[1,2,4]triazole-3,5-diamine analogues as novel and potent anti-
cancer cyclin-dependent kinase inhibitors: synthesis and evalu-
ation of biological activities. J Med Chem 48:4208–4211. doi:
10.1021/jm050267e
Manfredini S, Vicentini CB, Manfrini M, Bianchi N, Rutiliano C,
Mischiati C, Gambari R (2000) Pyrazolo-triazoles as light
activable DNA cleaving agents. Bioorg Med Chem 8:2343–
2346. doi:10.1016/S0968-0896(00)00160-7
Mathew V, Keshavayya J, Vaidya VP (2006) Heterocyclic system
containing bridgehead nitrogen atom: synthesis and pharmaco-
logical activities of some substituted 1,2,4-triazolo[3,4-b]-1,3,
4-thaidiazole. Eur J Med Chem 41:1048–1058. doi:10.1016/
j.ejmech.2006.03.018
Medarde M, Maya AB, Perez-Melero C (2004) Naphthalene com-
bretastatin analogues: synthesis, cytotoxicity and antitubulin
activity. J Enzyme Inhib Med Chem 19:521–540
Menegatti R, Cunha AC, Ferreria VF, Perreira EFR, El-Nabawi A,
Eldefrawi AT, Albuquerque EX, Neves G, Rates SMK, Fraga
CAM, Barreiro EJ (2003) Design, synthesis and pharmacological
profile of novel dopamine D2 receptor ligands. Bioorg Med
Chem 11:4807–4813. doi:10.1016/S0968-0896(03)00487-5
Micetich RG, Maiti SN, Spevak P, Hall TW, Yamabe S, Ishida N,
Tanaka M, Yamabe S, Tanaka M, Yamazaki T, Nakai A, Ogawa
K (1987) Synthesis and beta-lactamase inhibitory properties of 2
beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam-3 alpha-
carboxylic acid 1,1-dioxide and related triazolyl derivatives.
J Med Chem 30:1469–1474. doi:10.1021/jm00391a032
Nefzi A, Ostresh JM, Houghten RA (1997) The current status of
heterocyclic combinatorial libraries. Chem Rev 97:449–472. doi:
10.1021/cr960010b
Olesen PH, Sorensen AR, Urso B, Kurtzhals P, Bowler AN, Ehrbar U,
Hansen BF (2003) Synthesis and in vitro characterization of 1-(4-
aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-
carboxylic acid derivatives: a new class of selective GSK-3
inhibitors. J Med Chem 46:3333–3341. doi:10.1021/jm021095d
Parmar SS, Gupta AK, Singh HH, Gupta TK (1972) Benzimidazolyl-
1,2,4-(H)-triazoles as central nervous system depressants. J Med
Chem 15:999–1000. doi:10.1021/jm00279a033
Peng H, Kumaravel G, Yao G, Sha L, Wang J, Vlijmen V, Bohnert T,
Huang C, Vu CB, Ensinger CL, Chang H, Engber TM, Whalley
ET, Petter RC (2004) Novel bicyclic piperazine derivatives of
triazolotriazine and triazolopyridines as highly potent and
selective adenosine A2A receptor antagonists. J Med Chem
47:6218–6229. doi:10.1021/jm0494321
Russell MGN, Carling RW, Atack JR, Bromidge FA, Cook SM, Hunt
P, Lsted C, Lucas M, McKernan RM, Mitchinson A, Moore KW,
Thomas D, Thompson S, Wafford KA, Casro JL (2005)
Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-
ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor
agonists at the alpha3 subunit. J Med Chem 48:1367–1383. doi:
10.1021/jm040883v
Dabak K, Sezer O, Akar A, Anac
investigation of tuberculosis inhibition activities of some 1,2,3-
triazole derivatives. Euro Med Chem 38:215–218. doi:
10.1016/S0223-5234(02)01445-9
O (2003) Synthesis and
J
Demange L, Boeglin D, Moulin A, Mousseau D, Ryan J, Berge G,
Gagne D, Heitz A, Perrissoud D, Locatelli V, Torsello A,
Galleyrand J, Martinez J (2007) Synthesis and pharmacological
in vitro and in vivo evaluations of novel triazole derivatives as
ligands of the ghrelin receptor 1. J Med Chem 50:1939–1957.
doi:10.1021/jm070024h
Desai NC, Chhabria MT, Dodiya AM, Bhavsar AM (2010) Synthesis,
characterization, anticancer activity, and QSAR-studies of some
new tetrahydropyrimidines. Med Chem Res. doi:10.1007/
s00044-010-9481-4 (Accepted for publication)
Desai NC, Dodiya AM, Kumar M, Bhatt NB (2010) Dimeric 2-(2-
chlorophenyl)-quinazolin-4-ones as potential antimicrobial agents.
Med Chem Res. doi:10.1007/s00044-011-9621-5 (Accepted for
publication)
Desai NC, Dodiya AM, Makwana AH (2011) Antimicrobial screen-
ing of novel synthesized benzimidazole nucleus containing
4-oxo-thiazolidine derivatives. Med Chem Res. doi:10.1007/
s00044-011-9752-8 (Accepted for publication)
Desai NC, Dodiya A, Rajpara KM, Rupala YM (2011) Synthesis and
antimicrobial screening of 1,3,4-oxadiazole and clubbed thio-
phene derivatives. J Saudi Chem Soc. doi:10.1016/j.jscs.2011.
06.020 (Accepted for publication)
Ebdrup S, Olsen OH, Jacobsen P, Sorensen LG (2004) Synthesis and
structure-activity relationship for a novel class of potent and
selective carbamoyl-triazole based inhibitors of hormone sensi-
tive lipase. J Med Chem 47:400–410. doi:10.1021/jm031004s
Haber J (2001) Present status and perspectives on antimycotics with
systemic effects. Cas Lek Cesk 140:596–604
Harpstrite SE, Collins SD, Oksman A, Goldberg DE, Sharma V
(2008) Synthesis, characterization, and ant malarial activity of
novel Schiff-base-phenol and naphthalene-amine ligands. Med
Chem 4:392–395
Holla BS, Kalluraya B, Sridhar KR, Drake E, Thomas LM, Bhandary
KK, Levine MS (1994) Synthesis, structural characterization,
crystallographic analysis and antibacterial properties of some
nitrofuryl triazolo[3, 4-b]-1,3,4-thiadiazines. Eur J Med Chem
29:301–308. doi:10.1016/0223-5234(94)90100-7
Ismaiel AM, Dukat M, Law H, Kamboj R, Fan E, Lee DKH,
Mazzocco L, Buekschkens D, Teitler M, Pierson ME, Glennon
AR (1997) 2-(1-Napthyloxy)ethylamines with enhanced affinity
for human 5-HT1DB (h5-HT1B) serotonin receptors. J Med Chem
40:4415–4419. doi:10.1021/jm970507t
Jenkins TJ, Guan B, Dai M, Li G, Lightburn TE, Huang S, Freeze BS,
Burdi DF, Jacutin-Porte S, Bennett R, Chen W, Minor C, Ghosh
S, Blackburn C, Gigstd KM, Jones M, Kolbeck R, Yin W, Smith
S, Cardillo D, Ocian TD, Harriman GC (2007) Design, synthesis,
and evaluation of naphthalene-sulfonamide antagonists of human
CCR8. J Med Chem 50:566–584. doi:10.1021/jm061118e
Kelley JL, Koble CS, Davis RG, McLean EW, Soroko FE, Cooper
BR (1995) 1-(Fluorobenzyl)-4-amino-1H–1,2,3-triazolo[4,5-
c]pyridines: synthesis and anticonvulsant activity. J Med Chem
38:4131–4134. doi:10.1021/jm00020a30
Sahin G, Palaska E, Kelicen P, Altmok G (2001) Synthesis of some
new 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiaz-
oles and 1,2,4-triazole-3-thiones and their anti-inflammatory
activities. Arzneim Forsch 51:478–484
Tandon VK, Singh KA, Goswamy GK (2004) 1- and 2-substituted
napthalenes: a new class of potential hypotensive agents. Bioorg
Med Chem Lett 14:2797–2800. doi:10.1016/j.bmcl.2004.03.080
Terrett NK, Gardner M, Gordon DW, Kobeylecki RJ, Steele J (1995)
Combinatorial synthesis—the design of compound libraries and
their application to drug discovery. Tetrahedron 51:8135–8173.
doi:10.1016/0040-4020(95)00467-M
Krchnak V, Holladay MW (2002) Solid phase heterocyclic chemistry.
Chem Rev 102:61–92. doi:10.1021/cr010123h
Li Z, Yang Q, Qian X (2005) Synthesis, antitumor and DNA
photocleaving activities of novel naphthalene carboxamides:
effects of different thio heterocyclic rings and aminoalkyl side
123

Med Chem Res (2012) 21:2981–2989
2989
Wellington K, Faulds DM (2002) Anastrozole: in early breast cancer.
Drugs 62:2483–2490
Wilson Gisvold’s (2004) Textbook of organic medicinal and phar-
maceutical chemistry. Lippincott, Williams and Wilkins, Phil-
adelphia, p 255
Zhan P, Liu X, Fang Z, Li Z, Pannecouque C, Clercq ED (2009)
Synthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2-
yl)-1,2,3-thiadiazol-5-ylthio)-N-acetamides as novel non-nucle-
oside HIV-1 reverse transcriptase inhibitors. Euro J Med Chem
44:4648–4653. doi:10.1016/j.ejmech.2009.06.037
123