Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors

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Exploring synthetic and therapeutic prospects of

new thiazoline derivatives as aldose reductase

(ALR2) inhibitors†

Cite this: RSC Adv., 2021, 11, 17259

cg

Muhammad Tariq Shehzad,‡^aAqeel Imran, ‡^bAbdul Hameed,

Mariya al Rashida, ^cMarium Bibi,^dMaliha Uroos,^eAsnuzilawati Asari,^fShaﬁa Iftikhar,^g

Habsah Mohamad, Muhammad Nawaz Tahir, Zahid Shaﬁq ^aand Jamshed Iqbal

h

i

b

*

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for

the development of new antidiabetic agents. With our ongoing interest towards aldose reductase (ALR2)

inhibition, we have synthesized and screened a series of thiazoline derivatives (5a–k, 6a–f, 7a–1 & 8a–j)

to ﬁnd a lead as a potential new antidiabetic agent. The bioactivity results showed the thiazoline-based

compound 7b having a benzyl substituent and nitrophenyl substituent-bearing compound 8e were

identiﬁed as the most potent molecules with IC₅₀values of 1.39 ꢀ 2.21 mM and 1.52 ꢀ 0.78 mM

respectively compared with the reference sorbinil with an IC₅₀value of 3.14 ꢀ 0.02 mM. Compound 7b

with only 23.4% inhibition for ALR1 showed excellent selectivity for the targeted ALR2 to act as

a potential lead for the development of new therapeutic agents for diabetic complications.

Received 4th March 2021

Accepted 29th April 2021

DOI: 10.1039/d1ra01716k

rsc.li/rsc-advances

patients without diabetes [00]. In case of progression of this

disease severe diabetic complications result such as neuropathy,

1 Introduction

nephropathy, mood disorders, diabetic retinopathy. These

complications are generally a result of hyperglycemia⁷which

initiates the polyol pathway due to non-insulin dependent

glucose uptake. This pathway primarily involves NADPH depen-

dent reduction of glucose to sorbitol, the enzyme responsible for

this reduction is aldose reductase (AR; ALR2; EC 1.1.1.21)

belonging to aldo-keto reductase enzyme superfamily. The

sorbitol in turn converts metabolically via another enzyme

sorbitol dehydrogenase into fructose, resulting in increase in the

glucose ux.⁸High glucose level in diabetes promotes the

combination of glucose to ALR2 and metabolized about one third

of the total glucose to sorbitol via the polyol pathway in tissues

such as retina, lens, peripheral nerves and kidneys. As a result,

the regulated polyol pathway accumulates the sorbitol in cells

causing swelling of cell, osmotic imbalance and changes in

permeability of membrane. Sorbitol does not penetrate the

cellular membranes especially that of eye lens. Moreover, the

drastic lessening of NAD⁺and NADPH alters the cellular redox

potentials and weakens the enzymatic activities like that of

glutathione reductase and nitric oxide synthase (NOS); worsening

the intracellular oxidative stress level. Stress level is also

increased via free radicals produced from a number of radical

precursors like protein kinase C (PKC) isomer, advanced glyca-

tion end products (AGEs), poly-ADP-ribose polymerase (PARP)

and mitogen-activated protein kinase (MAPK). High level of free

radicals damages a number of tissues. Hence, all the oxidative

stress reactions mediated by ALR2 along with the polyol pathway

represent important pathogenesis of diabetic complications.⁹

The incidence of Diabetes mellitus (DM) disease is increasing

alarmingly and more than 400 million people are aﬀected all over

the world.¹Diabetes complications aﬀect about 25% of the

elderly population over the age of 65, and this proportion is

steadily growing.²The majority of the population aﬀected with

DM belongs to under-developed or developing regions of the

world.^3–6According to a recent study between COVID-19 and

diabetes, the COVID-19 patients with diabetes have a two-fold

higher risk of mortality and disease incidence than COVID-19

^aInstitute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800,

Pakistan. E-mail: zahidshaq@bzu.edu.pk

^bCentre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad

Campus, Abbottabad, 22060, Pakistan. E-mail: drjamshed@ciit.net.pk;

jamshediqb@googlemail.com

^cDepartment of Chemistry, Forman Christian College (A Chartered University),

Ferozepur Road, Lahore, 54600, Pakistan

^dDepartment of Biosciences, 90 and 100 Clion, Shaheed Zulkar Ali Bhutto Institute

of Science and Technology, Block 5, Clion, Karachi, 75600, Pakistan

^eInstitute of Chemistry, University of the Punjab, Lahore, 54590, Pakistan

^fFaculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030,

Kuala Nerus, Terengganu, Malaysia

^gDepartment of Chemistry, University of Sahiwal, Sahiwal, 57000, Pakistan

^hInstitute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030, Kuala

Nerus, Terengganu, Malaysia

ⁱDepartment of Physics, University of Sargodha, Sargodha, Pakistan

† Electronic supplementary information (ESI) available: Supplementary

information includes the bioactivity protocol, docking protocol and NMR

spectra of some compounds. See DOI:10.1039/d1ra01716k

‡ Both authors contributed equally.

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From aldo-keto reductase (AKR), those reducing the alde- biologically important nucleus is expected to enhance their bio-

hydes are called aldehyde reductases (ALR1, EC 1.1.1.2) while logical potential. In view of this and in search of novel bioactive

those involved in the reduction of ketones are termed as molecules, the study was designed and aimed to prepare

ketoreductases (also belonging to AKR family). Both enzymes a number of various thiazolines possessing benzoxazinone,

have almost similar structure diﬀering just in their active sites.¹⁰adamantyl, benzodioxane and indole moieties to evaluate their

The one accurately capable to reduce the aldehyde functionality enzyme inhibition potential with an expectation that they may

of glucose in polyol pathway is ALR1. This enzyme is also display more potent activity and thus result into the development

involved in metabolism of 3-deoxyglucosone and methyl glyoxal of diﬀerent compounds of medicinal interest.

causing toxic glycation end products. In contrast, it also assists

the reductive detoxication of reactive aldehydes. An example is

the reduction of aldehyde phospholipids to regulate the pro-

2. Results and discussion

inammatory response.¹¹

2.1 Chemistry of thiazolines derivatives 5a–k, 6a–f, 7a–i and

There are a number of studies reported the aldose reductase

8a–j

inhibitors (ARIs).^12–17Up to yet now, only one ARI drug; Epal-

In the current study, the thiazoline derivatives 5–8 were

designed and prepared in variable yields (76–92%) by using four

diﬀerent types of carbonyl group bearing compounds 1 i.e. 6-

acetyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 1-acetyl adamantane,

restat, ONO Pharmaceutical, Osaka, Japan has been mar-

keted.^18,19Though the polyol pathway inhibition is more

challenging to reduce the complications of diabetes; some iso-

lated natural products have been used as potent ARIs. Some

synthesized compounds have same active functionalities as that

of potent natural product and have been entered in to clinical

trials (Fig. 1). It is of utmost importance to develop potent and

selective ARIs (ALR1 and ALR2 share about 65% sequence

homology), which can regulate the polyol pathway and combat

secondary diabetic complications.^20,21The present work focuses

on the synthesis of a series of novel thiazoline based inhibitors

and their evaluation as ARIs.

The compounds containing benzoxazinone, adamantyl, ben-

zodioxane and indole nuclei have been synthesized and investi-

gated for their diverse biological activities as many of these

moieties are also the part of bioactive natural products.^22–33

Incorporation or conjugation of thiazoline moieties with another

1,4-benzodioxan-6-yl

methyl

ketone

and

indole-3-

carboxaldehyde. The starting materials bearing carbonyl

group were treated in equimolar quantities with N-substituted

thiosemicarbazides 2 in methanol as solvent. The reaction was

catalyzed by using glacial acetic acid as catalyst to get thio-

semicarbazones

3

as intermediate.^34,35Further, the thio-

semicarbazone derivatives 3 were reacted with a range of 4-

substituted 2-bromoacetophenones 4 in solvent ethanol along

with sodium acetate. The resulting mixture was heated at reux

till the complete consumption of starting material, monitored

by TLC analysis. The pure product was obtained via recrystal-

lization from absolute ethanol (Scheme 1).

The structures of thiazoline derivatives (5a–k, 6a–f, 7a–i and

8a–j) were conrmed by using diﬀerent spectroscopic

Fig. 1 Examples of some known ALR2 inhibitors.

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Scheme 1 Preparation of thiazoline derivatives 5a–k, 6a–f, 7a–i and 8a–j.

Fig. 2 The X-ray crystal structure of thiazoline derivative 5h. Note: the ORTEP diagram of 5h drawn at 50% probability level with H-atoms as

small circles of arbitrary radii. The minor disordered parts of chloroform are not shown for clarity.

techniques that include IR spectra, NMR spectroscopy and 3184–3338 cm^ꢁ1, carbonyl group (C]O) of lactam moiety at

microanalysis (CHN). The infrared spectra of a typical thiazo- 1663–1748 cm^ꢁ1and imine group C]N bands were appeared at

lines from 5a–k series showed a stretching band of NH group at 1578–1593 cm^ꢁ1regions consequently, the compounds in

Fig. 3 The X-ray crystal structure of thiazoline derivative 7i. Note: the ORTEP diagram of 7i drawn at 50% probability level with H-atoms as small

circles of arbitrary radii. The minor disordered part is not shown for clarity.

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Table 1 Thiazoline derivatives 5a–k, 6a–f, 7a–i and 8a–j

Table 1 (Contd.)

Compound

R

R₁

R₂

X

Compound

R

R₁

R₂

X

5a

CH₃C₆H₅

Br

5j

CH₃3-OCH₃C₆H₄

Cl

5b

5c

5d

5e

5f

CH₃3-OCH₃C₆H₄

Br

5k

6a

CH₃4-FC₆H₄

Cl

Br

CH₃2,6-(CH₃)₂C₆H₃Br

CH₃C₆H₅

6b

6c

6d

6e

6f

CH₃C₁₀H₇

Br

CH₃2-CH₃C₆H₄

Br

CH₃2-CH₃C₆H₄

CH₃C₆H₅

NO₂

CH₃2,6-(CH₃)₂C₆H₃Br

CH₃C₆H₅CH₂

Cl

CH₃3-OCH₃C₆H₄

CH₃2,6-(CH₃)₂C₆H₃Cl

5g

5h

5i

CH₃4-FC₆H₄

7a

7b

7c

CH₃C₆H₅

Br

CH₃C₆H₅CH₂

CH₃2,6-(CH₃)₂C₆H₃NO₂

CH₃2,6-(CH₃)₂C₆H₃Br

CH₃C₆H₅

Cl

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Table 1 (Contd.)

Compound

R

R₁

R₂

X

Compound

R

R₁

R₂

X

7d

CH₃4-FC₆H₄

NO₂

8d

H

C₆H₅

NO₂

Cl

7e

7f

CH₃C₆H₅CH₂

NO₂

8e

8f

H

C₆H₅CH₂

3-OCH₃C₆H₄

C₆H₅

CH₃2,6-(CH₃)₂C₆H₃NO₂

7g

7h

7i

CH₃C₆H₅

Cl

CH₃4-FC₆H₄

8g

8h

8i

CH₃C₆H₅CH₂

C₆H₅CH₂

Cl

8a

8b

8c

H

C₆H₅

Br

4-FC₆H₄

Cl

C₆H₁₁

Br

8j

H

2,6-(CH₃)₂C₆H₃Cl

4-FC₆H₄

NO₂

thiazoline series 6a–f and 7a–i, showed imine group (C]N) in

the range of 1558–1617 cm^ꢁ1. Furthermore, the indole-based

thiazolines 8a–j, showed NH stretching band at 3125–

3444 cm^ꢁ1while C]N bond in the range of 1603–1615 cm^ꢁ1

The proton H-NMR spectra of diﬀerent thiazoline series 5a–k

and 8a–j, displayed broad singlets for lactam NH and indole NH

.

1

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Table 2 In vitro Inhibitory activity of thiazoline derivatives against Aldehyde (ALR1) and Aldose (ALR2) reductase enzymes

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

5a

13.4%

22.6%

5b

27.4%

31.9%

5c

5d

5e

5f

22.7%

12.4%

19.5%

6.7%

20.83%

31.4%

3.13 ꢀ 1.45

3.24 ꢀ 2.72

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

5g

31.73%

24.7%

5h

18%

19.6%

5i

16.77%

31.3%

5j

5.16%

32.8%

5k

35.19%

22.6%

6a

4.40 ꢀ 1.45

3.29 ꢀ 1.47

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

6b

12.9 ꢀ 0.39

4.93 ꢀ 1.86

6c

10.19 ꢀ 1.35

4.07 ꢀ 2.35

6d

4.21 ꢀ 2.35

11.6%

6e

2.18 ꢀ 0.83

33.5%

6f

3.51 ꢀ 2.31

19.7%

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

7a

5.96 ꢀ 1.05

1.39 ꢀ 2.21

3.14 ꢀ 1.87

11%

23.7%

23.4%

33.4%

4.5%

7b

7c

7d

7e

14%

23.6%

7f

23%

21.7%

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

7g

14.49 ꢀ 1.49

3.14 ꢀ 0.41

7h

9.63 ꢀ 1.21

2.94 ꢀ 1.73

7i

29.62 ꢀ

2.20 ꢀ 0.92

8a

13.4%

15.6%

8b

37.4%

29.4%

8c

6.74%

35.4%

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

8d

31%

18.6%

8e

1.52 ꢀ 0.78

2.94 ꢀ 1.34

8f

4.21 ꢀ 1.63

12.4%

8g

5.16%

23.5%

8h

10.32%

33.4%

8i

23.22%

12.5%

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Table 2 (Contd.)

ALR2

ALR1

Code

Structure

IC₅₀(mM) ꢀ SEM^a/Percent inhibition

8j

34.83%

27.8%

Valproic acid^b

Sorbinil^b

—

57.4 ꢀ 0.89

3.14 ꢀ 0.02

—

a

b

Half maximal inhibitory concentration. Standard inhibitor.

group in the range from d_H10.78–10.83 and d_H11.51–

10.55 ppm, respectively. The singlet of thiazoline –CH–

appeared in the range of d_H5.79–7.01 ppm. The other of

diﬀerent protons in all the series of thiazolines were in well

agreement to conrm the structures of desired compounds.

Moreover, the crystal structure of the compounds 5h and 7i

further conrm the structure of thiazoline derivatives (Fig. 2, 3)

(Table 1).

2.2 Biological activity

The synthetic thiazoline derivatives (5a–k, 6a–f, 7a–1 & 8a–j)

were tested against aldehyde reductase enzyme (ALR1), and

their anti-diabetic potential by evaluating inhibitory activity

against aldose reductase (ALR2). Results indicated that out of

thirty six compounds tested, eight of them, 5f, 6a, 6b, 6c, 7g, 7h,

7i, and 8e were found active inhibitors of ALR2 and ALR1

Fig. 4 Selective ALR2 inhibitory activity of thiazoline derivatives (6d, 6e, 6f, 7a, 7b and 8f).

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Fig. 5 ALR1/ALR2 inhibitory activities of adamantyl substituted compounds 6a, 6b & 6c.

enzymes (Table 2). However, compound 6d, 6e, 6f, 7a, 7b, 7c and with IC₅₀values 4.21 ꢀ 2.35 mM, 2.18 ꢀ 0.83 mM and 3.51 ꢀ 2.31

8f were identied as selective ALR2 inhibitors (Fig. 4). mM respectively. Compounds 6a, 6b and 6c were also found to

Compound 5f, one of the 2H-1,4-benzoxazin-3(4H)-one be active against ALR1 and ALR2 enzymes (Fig. 5).

bearing derivatives were active against ALR1 and ALR2 having Among the series, compound 7b showed high inhibition

IC₅₀value of 3.13 ꢀ 1.45 mM and 3.24 ꢀ 2.72 mM, respectively. potential against ALR2 (IC₅₀¼ 1.39 ꢀ 2.21 mM). However,

The substitution of nitrophenyl with bromophenyl or chlor- compound 7b was found to have considerably selective activity

ophenyl, as in compound 5b and 5j, showed weak activity against ARL2 exhibiting only 23.4% inhibition against ALR1.

against both ARL1 and ARL2 enzymes in comparison to sorbinil The inhibition potential of chlorophenyl substituted thiazoline

and valproic acid with respective IC₅₀values of 3.14 ꢀ 0.02 mM derivative 7i against ALR2 was much lower than the afore-

and 57.4 ꢀ 0.89 mM (Table 2).

mentioned compound with IC₅₀of 38.2 ꢀ 1.43 mM. Further-

In general, compounds (6a–6f) containing adamantane more, an improved inhibitor potency of compound 7i was also

substituent demonstrated the most promising activity among observed against ALR1 (IC₅₀4.01 ꢀ 0.39 mM).

all the derivatives. Out of six, three compounds 6d, 6e and 6f

Among the indolyl substituted thiazoline derivatives,

showed a good inhibitory activity and selectively against ALR2 compound 8e having a nitrophenyl moiety showed high

Fig. 6 Bioactivity of indolyl substituted thiazoline derivatives.

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free energy using HYDE utility (part of LeadIT soware), the

conformation with most favorable binding free energy was

retained for further analysis The crystal structures of porcine

ALR1 (ref. 37) and human ALR2 (ref. 38) were downloaded from

˚

the Protein Data Bank [PDB ids: 3FX4 at 1.99 A and 1US0 at 0.66

39

˚

A respectively]. Docking protocol was validated by re-docking

of the co-crystallized ligand. The docking protocol was able to

reproduce the experimentally bound conformation of co-

crystallized ligand (FX4) with an rmsd of 1.03. For docking

against ALR1, three of the most active inhibitors 7h, 7i and 8e

were selected. All compounds were found to bind in the same

area of the binding pocket as the co-crystallized inhibitor FX4

(Fig. 7).

By analyzing the binding site interactions of the co-

crystallized

ligand

(ALR1

inhibitor),

FX4

([5-(3-

carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-

yl]acetic acid) it can be seen that the amino acid residues that

are important for binding are Arg312, Phe298, Trp220, Trp22,

Arg309, and Ala219. When docking studies of ALR1 inhibitors

(7h, 7i, 8e) were carried out, same amino acids were found to be

Fig. 7 Overlap of ALR1 inhibitors 7h (dark pink), 7i (purple) and 8e (light

pink) with the co-crystallized inhibitor FX4 ([5-(3-carboxymethoxy-4-

methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid) (black),

NADP is shown in grey.

inhibitory potency against ARL2 and ARL1, with IC₅₀values of involved in binding these inhibitors (Table S1†). Fig. S1† shows

1.52 ꢀ 0.78 mM and 2.94 ꢀ 1.34 mM respectively. However, the the docked conformation of compound 7h. The oxygen atom of

inhibitory activity of chlorophenyl substituted thiazoline the benzodioxane ring was making hydrogen bond with

derivative 8h, was weakened for both enzymes ALR2 and ALR1 Met302. The nitrogen atom of the C]N moiety next to the

demonstrating 10.32% and 33.4% inhibition respectively. thiazole ring was making a hydrogen bond with Arg312. The OH

Furthermore, the compound 8f was a selective ALR2 inhibitor group of Tyr50 was acting as a hydrogen bond donor towards

than ALR1 exhibiting only 12.4% inhibition (Fig. 6). The other the uorine atom. The carbonyl oxygen atom of Tyr 50 was

indolyl substituted compounds (8a, 8b, 8c, 8d, 8g, 8h, 8i, & 8j) acting as a halogen bond acceptor towards the chlorine atom. A

were found inactive with less than 50% inhibitory activity number of hydrophobic interactions were also observed.

against ALR2 as well against ARL1 enzymes.

Phe125 was making pi–pi stacked interactions with the thiazole

and the phenyl ring attached to thiazole ring. Ile299 was making

alkyl and pi-alkyl interactions with the methyl group and the

phenyl ring of benzodioxane ring respectively. Ile49 was making

pi-alkyl interactions with both chlorophenyl and uorophenyl

rings, whereas Trp114 was making pi-alkyl interaction with the

methyl group.

3. Docking studies

3.1 Molecular docking studies of ALR1 and ALR2 inhibitors

To rationalize the mode of binding and nature of binding site

interactions, molecular docking studies were carried out using

BioSolveIT's LeadIT soware.³⁶For each inhibitor, the top 10

docked conformations were further evaluated for their binding

Docking of compound 7i revealed hydrogen bonded inter-

actions between the oxygen atom of the benzodioxane ring and

Fig. 8 Docked conformation of ALR2 inhibitor 7b.

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Fig. 9 Docked conformation of ALR2 inhibitor 8e.

Val300, and between the nitrogen atom of the C]N group and thiazole ring, whereas the sulfur atom of Cys298 was making pi-

Met302 (Fig. S2†). A number of hydrophobic interactions were sulfur contact with the benzyl ring.

also observed. Ile299 was making alkyl and pi-alkyl interactions

with the methyl group and phenyl ring of benzodioxane ring observed. Trp20 was within hydrogen bond distance (1.99 A and

For compound 7b (Fig. 8), similar interactions were

˚

respectively. Pro301 was making also alkyl interaction with the 2.12 A) of both nitrogen atoms of C]N groups. Hydrophobic

methyl group. Lys23 was alkyl interaction with the chlorine interactions include Trp111 making a pi–pi stacked interaction

atom and pi-alkyl interaction with chlorophenyl ring. Arg218 with the bromo phenyl ring and a pi-alkyl interaction with the

was making pi-alkyl interaction with the phenyl ring of benzo- bromine atom. Trp20 was making a pi–pi T-shaped interaction

dioxane ring, whereas Ala219 was making pi-alkyl interaction with the thiazole ring. Pro218 was making a pi-alkyl interaction

with the thiazole ring.

with the methyl group. Leu300 was making pi-alkyl interaction

Docking of compound 8e revealed two hydrogen bonds of with both benzyl and bromo phenyl ring, whereas Val47 was

Arg309 and Arg312 with nitrogen atom of C]N bond and making pi-alkyl interaction with the thiazole ring. A pi-sulfur

oxygen atom of the nitro group (Fig. S3†). Notable hydrophobic interaction was also observed between Tyr48 and the sulfur

interactions include pi-sigma and pi-alkyl interaction of Ile49 atom of thiazole ring.

with indole phenyl ring and pyrrole ring of indole respectively.

Docking of compound 8e was also carried out, its docked

Tyr50 was making pi–pi stacked interaction with pyrrole ring of conformation along with binding site interactions are shown in

indole. Ile299 and Met302 were making pi-alkyl interactions Fig. 9. Both oxygen atoms of the nitro group were making

with thiazole ring and nitro phenyl ring respectively.

hydrogen bonds with Trp111 and Tyr48, His110 is also within

Docking studies of ALR2 inhibitors were also carried out for hydrogen bond distance to the nitro group. It is important to

most active inhibitors 6e, 7b and 8e. Prior to docking, the note that Trp111, Tyr48 and His110 are the same amino acids

docking protocol was veried by re-docking the co-crystallized that are involved in binding the carboxylate group of standard

ligand LDT ({2-[(4-bromo-2-uorobenzyl)carbamothioyl]-5- inhibitor LDT. Leu300 was making hydrophobic interactions,

uorophenoxy}acetic acid) from the ALR2 (PDB id: 1su0). The pi-sigma and pi-alkyl with pyrrole ring of indole, and the phenyl

docking protocol was able to reproduce the experimentally indole ring respectively. Phe122 was making pi–pi T-shaped

observed conformation of LDT with rmsd of <2. Moreover all interaction with both thiazole and indole rings. Another pi–pi

compounds were found to bind at the same region of the active T-shaped interaction was observed between Trp20 and nitro

site as that of the co-crystallized inhibitor LDT (Fig. S4†).

phenyl ring. Moreover, an intramolecular pi–pi T shaped

Docked conformation of compound 6e is shown in Fig. S5.† contact was also observed between the nitro phenyl and benzyl

The nitrogen atom of the C]N group was making a hydrogen ring, this orientation may additionally stabilize the binding of

bond with Trp20. A number of hydrophobic interactions were inhibitor. The nitro phenyl ring was also found to be involved in

observed that are deemed necessary for eﬃcient binding. a pi-alkyl interaction with Val47. An electrostatic attractive

Leu300 was making a pi-sigma interaction with the chloro interaction was observed between Lys77 and the oxygen atom of

phenyl ring. Trp20 was making pi–pi stacked and pi-alkyl the nitro group. Another electrostatic (pi-anion) interaction was

interactions with the benzyl ring and the methyl group respec- observed between Trp20 and same oxygen atom of the nitro

tively. Trp111 was making a pi-stacked interaction with the group.

chloro phenyl ring and a pi-alkyl interaction with the chloro

group. Two pi-sulfur interactions were also observed. Trp219

was making a pi-sulfur contact with the sulfur atom of the

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Fig. 10 Radius of gyration (R_g) of 1US0, protein plus cognate ligand (LDT) and protein plus selective compound (7b) during 50 ns MD-simulation

run.

Fig. 11 Root mean square deviation (RMSD) of 1US0, protein plus cognate ligand (LDT) and protein plus selective compound (7b) during 50 ns

MD-simulation run.

Fig. 12 Root mean square ﬂuctuation (RMSF) of 1US0, protein plus cognate ligand (LDT) and protein plus selective compound (7b) during 50 ns

MD-simulation run.

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under reux for 2–6 h. Upon completion of reaction, monitored

through TLC, the hot reaction mixture was cooled to room

temperature. The solid product obtained in each case was

ltered, washed several times with hot methanol and dried

under vacuum to aﬀord the desired thiosemicarbazones 3 in

pure form. The resultant thiosemicarbazone derivatives were

used as such in the next step without any further purication.

4. Molecular dynamics simulation

The conformational stabilities of the apoenzymes (ALR1 and

ALR2) and their protein + ligand complexes, both cognate and

test compounds, were performed to simulate protein exibility.

The structure of proteins (apoproteins) were rst subjected to

MD run of 50 ns and then docked poses of cognate ligands and

selected ligands (holoenzymes) were submitted to MD run for

50 ns. The time evolution of the radius of gyration of 3FX4 and

1US0, apoenzymes and holoenzymes, exposed in the applied

electric elds are shown in Fig. S6† and 10, respectively. The

graph indicating that the average value of R_gslightly uctuating

between 1.92–1.97 nm for ALR1 (3FX4), while for ALR2 (1US0),

the radius of gyration lies between 1.89 and 1.93 nm, signifying

a ne degree of compactness. The average values of RMSD over

a period 50 ns for 3FX4 and 1US0, apoenzymes and holoen-

zymes, exhibited minute uctuations, reaﬃrming stable

complex formation between enzymes and test compounds, as

shown in Fig. S7† and 11, respectively. RMSF analyzes the

portions of structure that are uctuating from their mean

structure the most (or least). The (RMSF) of ALR1 and ALR2 were

examined, it was observed that residues were found stable in

both the cases (Fig. S8,† and 12).

6.2 General procedure for the synthesis of thiazoline

derivatives (5–8)

A

mixture of equimolar amounts of appropriate thio-

semicarbazone derivative 3 (0.005 mol), 4-substituted (bromo,

nitro, chloro) phenacyl bromide 4 (0.005 mol) and anhydrous

sodium acetate (0.005 mol) in absolute ethanol (25 mL) was

heated under reux with continuous stirring for 12–24 h. The

reaction mixture was then partially concentrated on a rotary

evaporator and le overnight. The precipitate formed in each

case was ltered oﬀ, washed with warm diethyl ether, dried and

recrystallized from absolute ethanol to furnish the target thia-

zoline derivatives 5–8 in pure form.

The diﬀerent compounds are characterized as under:

6-((E)-1-((Z)-(4-(4-bromophenyl)-3-phenylthiazol-2(3H)-yli-

dene)hydrazono)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5a).

Yield 81%; m.p. 228–230 C; IR y_max(cm^ꢁ1): 3188 (N–H), 3022

ꢂ

5. Conclusions

(Ar-H), 2942 (CH₃), 1748 (C]O), 1581 (C]N), 1539, 1506 (Ar-

1

C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.13 (s, 3H, CH₃–

In this research, we have synthesized thiazoline derivatives (5a–

k, 6a–f, 7a–1 & 8a–j), which were tested against aldehyde

reductase (ALR1), and aldose reductase (ALR2) enzymes to study

their anti-diabetic potential. The results demonstrated that

compounds containing adamantyl substituent (6a–6f) have

most promising activity among all the derivatives. The

compound 7b (with benzyl substituent) among the series was

found signicantly selective against ARL2 with IC₅₀value of 1.39

ꢀ 2.21 mM compare to sorbinil, a reference inhibitor, with IC₅₀

values of 3.14 ꢀ 0.02 mM. Furthermore, the compounds 6e also

showed potency against ALR2 with IC₅₀values of 2.18 ꢀ 0.83

mM, whilst 6f presented slightly higher with IC₅₀value of 3.51 ꢀ

2.31 mM when compared with standard sorbinil. The compound

8e (with nitrophenyl substituent) demonstrated high potency

and selectivity against ALR2 enzyme with IC₅₀values of 1.52 ꢀ

0.78 mM. In silico molecular docking study was also performed

to further study the putative binding of active compounds with

the target enzyme to nd lead compound for further steps of

drug development.

C]N), 4.60 (s, 2H, O–CH₂–CO), 6.73 (s, 1H, CH-S), 6.96 (d, 1H, J

¼ 8.4 Hz, Ar-H), 7.12 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.28–7.36 (m, 4H,

Ar-H), 7.38–7.39 (m, 2H, Ar-H), 7.43–7.47 (m, 3H, Ar-H), 10.80 (s,

1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.82 (CH₃),

67.25 (OCH₂), 103.11 (S-CH]), 113.79 (Ar-C), 116.30 (Ar-C),

121.58 (Ar-C), 122.14 (Ar-C), 127.55 (Ar-C), 128.21 (Ar-C),

128.88 (Ar-C), 129.29 (Ar-C), 130.53 (Ar-C), 131.73 (Ar-C),

133.19 (Ar-C), 138.11 (Ar-C), 138.79 (Ar-C), 144.59 (N–C]),

155.60 (C]N–N), 165.13 (N–C]N), 168.69 (HN–C]O); anal.

calcd for C₂₅H₁₉BrN₄O₂S (519.41): C, 57.81; H, 3.69; N, 10.79;

found: C, 57.88; H, 3.65; N, 10.85.

6-((E)-1-((Z)-(4-(4-bromophenyl)-3-(3-methoxyphenyl)thiazol-

2(3H)-ylidene) hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-

one (5b). Yield 84%; m.p. 276–278 ^ꢂC; IR y_max(cm^ꢁ1): 3184 (N–

H), 3012 (Ar-H), 2950 (CH₃), 1690 (C]O), 1585 (C]N), 1536,

1

1509 (Ar-C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.15 (s,

3H, CH₃–C]N), 3.69 (s, 3H, OCH₃), 4.59 (s, 2H, O–CH₂–CO),

6.70 (s, 1H, CH–S), 6.75–6.77 (m, 1H, Ar-H), 6.86–6.88 (dd, 1H, J

¼ 0.8 Hz, 8.4 Hz, Ar-H), 6.94–6.97 (m, 2H, Ar-H), 7.14 (d, 2H, J ¼

2.0 Hz, Ar-H), 7.25 (t, 1H, J ¼ 8.0 Hz, Ar-H), 7.34 (dd, 1H, J ¼

2.4 Hz, 8.8 Hz, Ar-H), 7.42 (d, 1H, J ¼ 2.0 Hz, Ar-H), 7.47 (d, 2H, J

¼ 2.0 Hz, Ar-H), 10.78 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100

MHz) d ppm: 14.87 (CH₃), 55.77 (OCH₃), 67.25 (O–CH₂), 103.14

6 Experimental section

6.1 General procedure for the synthesis of

thiosemicarbazones (3)

A solution of corresponding aldehyde or ketone 1 (6-acetyl-2H- (S-CH]), 113.81 (Ar-C), 113.98 (Ar-C), 114.74 (Ar-C), 116.31 (Ar-

benzo[b][1,4]oxazin-3(4H)-one, 1-acetyl adamantane, 1,4- C), 120.87 (Ar-C), 122.13 (Ar-C), 127.56 (Ar-C), 129.87 (Ar-C),

benzodioxan-6-yl methyl ketone and indole-3-carboxaldehyde; 130.43 (Ar-C), 130.71 (Ar-C), 131.73 (Ar-C), 133.19 (Ar-C),

0.01 mol) in methanol (10 mL) was added to a hot stirred 138.79 (Ar-C), 139.09 (Ar-C), 144.61 (Ar-C), 155.70 (N–C]),

solution of appropriate N⁴-substituted thiosemicarbazide 2 159.75 (C]N–N), 165.13 (N–C]N), 168.55 (HN–C]O); anal.

(0.01 mol) in methanol (10 mL). Aer adding few drops of calcd for C₂₆H₂₁BrN₄O₃S (549.44): C, 56.84; H, 3.85; N, 10.20;

glacial acetic acid as catalyst, the reaction mixture was heated found: C, 56.80; H, 3.89; N, 10.24.

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1H, J ¼ 8.0 Hz, Ar-H), 7.35–7.43 (m, 2H, Ar-H), 7.79 (s, 1H, Ar-H),

7.82–7.84 (m, 2H, Ar-H), 8.12–8.14 (m, 2H, Ar-H), 10.82 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.49 (CH₃), 55.95

(OCH₃), 67.25 (O–CH₂), 94.87 (S-CH]), 103.19 (Ar-C), 113.46

(Ar-C), 114.01 (Ar-C), 116.07 (Ar-C), 117.16 (Ar-C), 121.70 (Ar-C),

123.63 (Ar-C), 126.06 (Ar-C), 127.56 (Ar-C), 128.71 (Ar-C), 133.14

(Ar-C), 140.39 (Ar-C), 147.51 (Ar-C), 149.61 (Ar-C), 157.01 (Ar-C),

157.40 (Ar-C), 159.20 (N–C]), 164.92 (C]N–N), 165.15 (N–C]

N), 167.07 (HN–C]O); anal. calcd for C₂₆H₂₁N₅O₅S (515.54): C,

60.57; H, 4.11; N, 13.58; found: C, 60.51; H, 4.15; N, 13.52.

6-((E)-1-((Z)-(3-(4-uorophenyl)-4-(4-nitrophenyl)thiazol-

6-((E)-1-((Z)-(4-(4-bromophenyl)-3-(2,6-dimethylphenyl)thia-

zol-2(3H)-ylidene) hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-

3(4H)-one (5c). Yield 80%; m.p. 260–262 ^ꢂC; IR y_max(cm^ꢁ1): 3246

(N–H), 3049 (Ar-H), 2935 (CH₃), 1695 (C]O), 1583 (C]N), 1541,

1

1487 (Ar-C]C); H-NMR (CDCl₃, 400 MHz) d ppm: 1.70 (s, 6H,

2ꢃCH₃-Ar), 2.29 (s, 3H, CH₃–C]N), 4.76 (s, 2H, O–CH₂–CO),

6.35 (s, 1H, CH–S), 7.06–7.10 (m, 3H, Ar-H), 7.17–7.19 (m, 2H,

Ar-H), 7.27–7.31 (m, 1H, Ar-H), 7.42–7.44 (m, 2H, Ar-H), 7.49–

7.51 (m, 1H, Ar-H), 7.54 (d, 1H, J ¼ 2.0 Hz, Ar-H), 7.86 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.45 (CH₃), 18.25

(2ꢃCH₃-Ar), 67.43 (OCH₂), 100.90 (S-CH]), 113.29 (Ar-C),

116.37 (Ar-C), 122.43 (Ar-C), 125.81 (Ar-C), 128.51 (Ar-C),

128.74 (Ar-C), 128.85 (Ar-C), 129.85 (Ar-C), 131.48 (Ar-C),

134.07 (Ar-C), 136.54 (Ar-C), 139.23 (Ar-C), 144.28 (N–C]),

155.54 (C]N–N), 164.94 (N–C]N), 166.68 (HN–C]O); anal.

calcd for C₂₇H₂₃BrN₄O₂S (547.47): C, 59.23; H, 4.23; N, 10.23;

found: C, 59.30; H, 4.25; N, 10.20.

2(3H)-ylidene) hydrazono)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-

one (5g). Yield 78%; m.p. 236–238 ^ꢂC; IR y_max(cm^ꢁ1): 3338 (N–

H), 3029 (Ar-H), 2964 (CH₃), 1659 (C]O), 1589 (C]N), 1557,

1

1508 (Ar-C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.10 (s,

3H, CH₃–C]N), 4.60 (s, 2H, O–CH₂–CO), 6.97 (s, 1H, CH–S),

7.05 (t, 2H, J ¼ 8.8 Hz, Ar-H), 7.31–7.38 (m, 3H, Ar-H), 7.43 (d,

1H, J ¼ 2.4 Hz, Ar-H), 7.82 (s, 1H, Ar-H), 7.86 (dd, 2H, J ¼ 1.6 Hz,

6.8 Hz, Ar-H), 8.15 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz, Ar-H), 10.83 (s,

1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.81 (CH₃),

67.24 (OCH₂), 94.60 (S-CH]), 113.91 (Ar-C), 115.28 (Ar-C),

115.51 (Ar-C), 116.33 (Ar-C), 121.69 (Ar-C), 123.65 (Ar-C),

127.55 (Ar-C), 128.78 (Ar-C), 130.48 (Ar-C), 130.57 (Ar-C),

133.13 (Ar-C), 135.53 (Ar-C), 144.75 (Ar-C), 147.56 (Ar-C),

149.36 (Ar-C), 157.06 (Ar-C), 159.27 (N–C]), 161.69 (C]N–N),

165.15 (N–C]N), 167.40 (HN–C]O); anal. calcd for C₂₅H₁₈

FN₅O₄S (503.50): C, 59.64; H, 3.60; N, 13.91; found: C, 59.68; H,

3.64; N, 13.85.

6-((E)-1-((Z)-(4-(4-bromophenyl)-3-(o-tolyl)thiazol-2(3H)-yli-

dene)hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5d).

Yield 86%: m.p. 294–296 C; IR y_max(cm^ꢁ1): 3285 (N–H), 3045

ꢂ

(Ar-H), 2942 (CH₃), 1701 (C]O), 1590 (C]N), 1570, 1510 (Ar-

1

C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.06 (s, 3H, CH₃-

Ar), 2.17 (s, 3H, CH₃–C]N), 4.59 (s, 2H, O–CH₂–CO), 6.73 (s, 1H,

CH–S), 6.96 (d, 1H, J ¼ 8.4 Hz, Ar-H), 7.08–7.10 (m, 2H, Ar-H),

7.17–7.19 (m, 2H, Ar-H), 7.30–7.34 (m, 3H, Ar-H), 7.41–7.44

(m, 3H, Ar-H), 10.78 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)

d ppm: 14.66 (CH₃), 18.05 (CH₃), 67.25 (OCH₂), 102.49 (S-CH]),

113.76 (Ar-C), 116.29 (Ar-C), 127.16 (Ar-C), 127.53 (Ar-C), 129.19

(Ar-C),, 129.72 (Ar-C), 130.31 (Ar-C), 130.35 (Ar-C), 131.33 (Ar-C),

131.74 (Ar-C), 133.22 (Ar-C), 136.49 (Ar-C), 137.32 (Ar-C), 139.00

(Ar-C), 144.53 (N–C]), 155.32 (C]N–N), 165.12 (N–C]N),

167.92 (HN–C]O); anal. calcd for C₂₆H₂₁BrN₄O₂S (533.44): C,

58.54; H, 3.97; N, 10.50; found: C, 58.50; H, 3.96; N, 10.54.

6-((E)-1-((Z)-(4-(4-nitrophenyl)-3-phenylthiazol-2(3H)-yli-

6-((E)-1-((Z)-(3-(2,6-dimethylphenyl)-4-(4-nitrophenyl)thia-

zol-2(3H)-ylidene) hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-

3(4H)-one (5h). Yield 81%; m.p. 218–220 ^ꢂC; IR y_max(cm^ꢁ1):

3200 (N–H), 3022 (Ar-H), 2957 (CH₃), 1687 (C]O), 1587 (C]N),

1570, 1498 (Ar-C]C); ¹H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.07

(s, 3H, CH₃–C]N), 2.12 (s, 6H, 2ꢃCH₃-Ar), 4.60 (s, 2H, O–CH₂–

CO), 6.97 (d, 1H, J ¼ 8.4 Hz, Ar-H), 7.06 (s, 1H, CH–S), 7.13–7.22

(m, 3H, Ar-H), 7.32–7.43 (m, 4H, Ar-H), 8.08 (dd, 2H, J ¼ 2.0 Hz,

6.8 Hz, Ar-H), 10.78 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)

d ppm: 14.69 (CH₃), 18.22 (2ꢃCH₃-Ar), 67.24 (OCH₂), 105.63 (S-

CH]), 112.75 (Ar-C), 113.78 (Ar-C), 116.30 (Ar-C), 121.60 (Ar-C),

124.08 (Ar-C), 127.53 (Ar-C), 128.58 (Ar-C), 129.46 (Ar-C), 133.07

(Ar-C), 136.47 (Ar-C), 136.90 (Ar-C), 138.03 (Ar-C), 143.19 (Ar-C),

144.59 (Ar-C), 147.39 (N–C]), 155.78 (C]N–N), 165.11 (N–C]

N), 166.58 (HN–C]O); fnal calcd for C₂₇H₂₃N₅O₄S (513.57): C,

63.14; H, 4.51; N, 13.64; found: C, 63.18; H, 4.54; N, 13.57.

6-((E)-1-((Z)-(4-(4-chlorophenyl)-3-phenylthiazol-2(3H)-yli-

dene)hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5i).

dene)hydrazono)ethyl)-2H_ꢂ-benzo[b][1,4]oxazin-3(4H)-one (5e).

Yield 87%; m.p. 296–298 C; IR y_max(cm^ꢁ1): 3240 (N–H), 3028

(Ar-H), 2959 (CH₃), 1685 (C]O), 1578 (C]N), 1544, 1494 (Ar-

1

C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.15 (s, 3H, CH₃–

C]N), 4.60 (s, 2H, O–CH₂–CO), 6.96 (d, 1H, J ¼ 8.4 Hz, Ar-

H),7.00 (s, 1H, CH–S), 7.32–7.36 (m, 4H, Ar-H), 7.36–7.49 (m,

5H, Ar-H), 8.09–8.11 (m, 2H, Ar-H), 10.80 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 100 MHz) d ppm: 14.90 (CH₃), 67.25 (OCH₂), 106.36

(S-CH]), 113.83 (Ar-C), 116.32 (Ar-C), 119.49 (Ar-C), 121.66 (Ar-

C), 123.96 (Ar-C), 127.57 (Ar-C), 128.35 (Ar-C), 128.71 (Ar-C),

129.39 (Ar-C), 129.42 (Ar-C), 133.06 (Ar-C), 137.51 (Ar-C),

138.02 (Ar-C), 144.68 (Ar-C), 147.16 (N–C]), 156.13 (C]N–N),

165.13 (N–C]N), 168.46 (HN–C]O); anal. calcd for

Yield 87%; m.p. 248–250 C; IR y_max(cm^ꢁ1): 3326 (N–H), 3054

ꢂ

(Ar-H), 2974 (CH₃), 1664 (C]O), 1587 (C]N), 1572, 1489 (Ar-

C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.09 (s, 3H, CH₃–

C

₂₅H₁₉N₅O₄S (485.51): C, 61.85; H, 3.94; N, 11.42; found: C,

1

61.80; H, 3.98; N, 11.36.

C]N), 4.60 (s, 2H, O–CH₂–CO), 6.59–7.08 (m, 2H, CH–S, Ar-H),

7.20 (t, 2H, J ¼ 7.2 Hz, Ar-H), 7.28–7.43 (m, 6H, Ar-H), 7.53–7.56

(m, 3H, Ar-H), 10.82 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)

d ppm: 14.81 (CH₃), 67.24 (OCH₂), 94.94 (S-CH]), 113.87 (Ar-C),

116.31 (Ar-C), 121.63 (Ar-C), 126.28 (Ar-C), 127.53 (Ar-C), 128.20

(Ar-C), 128.39 (Ar-C), 129.16 (Ar-C), 132.96 (Ar-C), 133.23 (Ar-C),

139.57 (Ar-C), 141.29 (Ar-C), 144.67 (N–C]), 156.57 (C]N–N),

165.16 (N–C]N), 167.36 (HN–C]O); anal. calcd for

6-((E)-1-((Z)-(3-(3-methoxyphenyl)-4-(4-nitrophenyl)thiazol-

2(3H)-ylidene) hydrazono)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-

one (5f). Yield 88%; m.p. 210–212 C; IR y_max(cm^ꢁ1): 3200 (N–

ꢂ

H), 3050 (Ar-H), 2948 (CH₃), 1664 (C]O), 1593 (C]N), 1561,

1

1485 (Ar-C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.13 (s,

3H, CH₃–C]N), 3.62 (s, 3H, OCH₃), 4.59 (s, 2H, O–CH₂–CO),

6.62–6.65 (m, 1H, Ar-H), 6.90–6.98 (m, 3H, CH–S, Ar-H), 7.08 (t,

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C₂₅H₁₉ClN₄O₂S (474.96): C, 63.22; H, 4.03; N, 11.80; found: C, 2.0 Hz, 6.8 Hz, Ar-H), 7.13 (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz, Ar-H), 7.22

63.25; H, 4.08; N, 10.76.

(dd, 1H, J ¼ 1.2 Hz, 7.2 Hz, Ar-H), 7.36 (t, 1H, J ¼ 7.6 Hz, Ar-H),

6-((E)-1-((Z)-(4-(4-chlorophenyl)-3-(3-methoxyphenyl)thiazol-

7.47–7.50 (m, 2H, Ar-H), 7.77–7.89 (m, 3H, Ar-H); ¹³C NMR

2(3H)-ylidene) hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)- (DMSO-d₆, 100 MHz) d ppm: 12.24 (CH₃), 28.43 (adamantane-C),

one (5j). Yield 79%; m.p. 228–230 C; IR y_max(cm^ꢁ1): 3320 (N– 36.96

(adamantane-C),

39.86

(adamantane-C),

40.26

ꢂ

H), 3045 (Ar-H), 2935 (CH₃), 1668 (C]O), 1593 (C]N), 1541, (adamantane-C), 97.91 (S-CH]), 123.84 (Ar-C), 125.34 (Ar-C),

1

1488 (Ar-C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.13 (s, 126.31 (Ar-C), 126.72 (Ar-C), 127.18 (Ar-C), 128.26 (Ar-C),

3H, CH₃–C]N), 3.63 (s, 3H, OCH₃), 4.60 (s, 2H, O–CH₂–CO), 128.82 (Ar-C), 129.04 (Ar-C), 131.26 (Ar-C), 134.27 (Ar-C),

6.62–6.65 (m, 1H, Ar-H), 6.87–6.97 (m, 3H, CH–S, Ar-H), 7.08 (t, 135.09 (Ar-C), 136.87 (Ar-C), 155.38 (N–C]), 166.17 (C]N–N),

1H, J ¼ 8.0 Hz, Ar-H), 7.32–7.37 (m, 3H, Ar-H), 7.42 (d, 1H, J ¼ 169.88 (N–C]N); anal. calcd for C₃₁H₃₀BrN₃S (556.56): C, 66.90;

1.6 Hz, Ar-H), 7.53–7.56 (m, 2H, Ar-H), 7.57 (s, 1H,Ar-H), 10.82 H, 5.43; N, 7.55; found: C, 66.95; H, 5.45; N, 7.52.

(s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.89 (CH₃),

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-4-(4-bro-

55.43 (OCH₃), 67.25 (O–CH₂), 95.04 (S-CH]), 111.65 (Ar-C), mophenyl)-3-(o-tolyl)-2,3-dihydrothiazole (6c). Yield 82%; m.p.

113.89 (Ar-C), 114.01 (Ar-C), 116.31 (Ar-C), 120.33 (Ar-C), 270–272 ^ꢂC; IR y_max(cm^ꢁ1): 3064 (Ar-H), 2954 (CH₃), 1617 (C]

121.66 (Ar-C), 127.54 (Ar-C), 128.41 (Ar-C), 128.89 (Ar-C), N), 1581, 1514 (Ar-C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm:

129.11 (Ar-C), 132.97 (Ar-C), 133.22 (Ar-C), 140.62 (Ar-C), 1.56 (bs, 6H, CH₃–C]N, CH₃-Ar), 1.66–1.72 (m, 6H, ada-

141.33 (Ar-C), 144.69 (Ar-C), 156.69 (N–C]), 159.11 (C]N–N), mantane –CH₂), 1.75–1.80 (bs, 6H, adamantane –CH₂), 2.00–

165.15 (N–C]N), 167.17 (HN–C]O); anal. calcd for C₂₆H₂₁

-

2.02 (bs, 3H, adamantane –CH₂), 6.12 (s, 1H, CH–S), 6.91–6.94

ClN₄O₃S (504.99): C, 61.84; H, 4.19; N, 11.09; found: C, 61.80; H, (m, 2H, Ar-H),7.02 (d, 1H, J ¼ 7.6 Hz, Ar-H), 7.09–7.13 (m, 1H,

4.24; N, 11.13.

Ar-H), 7.19–7.21 (m, 2H, Ar-H), 7.27–7.29 (m, 2H, Ar-H); ¹³C

NMR (DMSO-d₆, 100 MHz) d ppm: 13.00 (CH₃), 18.21 (CH₃-Ar),

6-((E)-1-((Z)-(4-(4-chlorophenyl)-3-(4-uorophenyl)thiazol-

2(3H)-ylidene) hydrazono) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)- 28.44

(adamantane-C),

36.96

(adamantane-C),

39.86

one (5k). Yield 78%; m.p. 230–232 ^ꢂC; IR y_max(cm^ꢁ1): 3310 (N– (adamantane-C), 40.36 (adamantane-C), 93.39 (S-CH]), 126.51

H), 3064 (Ar-H), 2932 (CH₃), 1663 (C]O), 1587 (C]N), 1529, (Ar-C), 127.32 (Ar-C), 128.11 (Ar-C), 128.84 (Ar-C), 129.23 (Ar-C),

1

1496 (Ar-C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.08 (s, 130.86 (Ar-C), 131.00 (Ar-C), 131.33 (Ar-C), 131.39 (Ar-C), 143.59

3H, CH₃–C]N), 4.59 (s, 2H, O–CH₂–CO), 6.54–7.06 (m, 3H, CH– (N–C]), 166.18 (C]N–N), 167.53 (N–C]N); anal. calcd for

S, Ar-H), 7.28–7.34 (m, 5H, Ar-H), 7.41–7.42 (m, 1H, Ar-H), 7.54–

C₂₈H₃₀BrN₃S (520.53): C, 64.61; H, 5.81; N, 8.07; found: C, 64.58;

7.57 (m, 3H, Ar-H), 10.81 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 H, 5.85; N, 8.12.

MHz) d ppm: 14.78 (CH₃), 67.25 (O–CH₂), 94.76 (S-CH]), 100.04

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-4-(4-

(Ar-C), 113.89 (Ar-C), 115.34 (Ar-C), 116.31 (Ar-C), 127.54 (Ar-C), bromophenyl)-3-(2,6-dimethylphenyl)-2,3-dihydrothiazole (6d).

128.45 (Ar-C), 129.18 (Ar-C), 130.41 (Ar-C), 130.49 (Ar-C), 133.20 Yield 90%; m.p. 254–256 C; IR y_max(cm^ꢁ1): 3059 (Ar-H), 2943

ꢂ

(Ar-C), 141.08 (Ar-C), 144.70 (Ar-C), 156.74 (Ar-C), 159.48 (N– (CH₃), 1617 (C]N), 1547, 1509 (Ar-C]C); ¹H-NMR (CDCl₃, 400

C]), 161.62 (C]N–N), 165.15 (N–C]N), 167.50 (HN–C]O); MHz) d ppm: 1.56 (s, 6H, CH₃–C]N, CH₃-Ar), 1.69–1.71 (m, 6H,

anal. calcd for C₂₅H₁₈ClFN₄O₂S (492.95): C, 60.91; H, 3.68; N, adamantane –CH₂), 1.77–1.80 (bs, 6H, adamantane –CH₂), 2.00–

11.37; found: C, 60.95; H, 3.65; N, 11.32.

2.02 (bs, 3H, adamantane –CH₂), 2.15 (s, 3H, CH₃-Ar), 6.13 (s,

1H, CH–S), 6.93 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.02 (d, 2H, J ¼ 7.2 Hz,

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-4-(4-

bromophenyl)-3-phenyl-2,3-dihydrothiazole (6a). Yield 81%; Ar-H), 7.12 (t, 1H, J ¼ 7.2 Hz, Ar-H), 7.28 (d, 2H, J ¼ 8.8 Hz, Ar-H);

m.p. 258–260 ^ꢂC; IR y_max(cm^ꢁ1): 3049 (Ar-H), 2965 (CH₃), 1616 ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 12.17 (CH₃), 18.17

(C]N), 1541, 1487 (Ar-C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm: (2ꢃCH₃–Ar), 28.27 (adamantane-C), 36.79 (adamantane-C),

1.67–1.75 (m, 6H, adamantane –CH₂), 1.81 (m, 6H, adamantane 39.67 (adamantane-C), 40.08 (adamantane-C), 100.18 (S-

–CH₂), 1.85 (s, 3H, CH₃–C]N), 2.01–2.02 (bs, 3H, adamantane CH]), 128.22 (Ar-C), 128.32 (Ar-C), 129.60 (Ar-C), 134.01 (Ar-C),

–CH₂), 6.11 (s, 1H, CH–S), 6.95 (d, 2H, J ¼ 8.8 Hz, Ar-H), 7.19– 136.01 (Ar-C), 136.53 (Ar-C), 138.77 (Ar-C), 143.56 (N–C]),

7.21 (m, 3H, Ar-H), 7.27–7.31 (m, 4H, Ar-H); ¹³C NMR (DMSO-d₆, 164.19 (C]N–N), 168.63 (N–C]N); anal. calcd for C₂₉H₃₂BrN₃S

100 MHz) d ppm: 12.48 (CH₃), 28.46 (adamantane-C), 36.98 (534.55): C, 65.16; H, 6.03; N, 7.86; found: C, 65.20; H, 6.09; N,

(adamantane-C), 39.94 (adamantane-C), 40.38 (adamantane-C), 7.80.

102.08 (S-CH]), 122.24 (Ar-C), 127.39 (Ar-C), 128.21 (Ar-C),

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-3-benzyl-

128.69 (Ar-C), 129.45 (Ar-C), 130.55 (Ar-C), 131.43 (Ar-C), 4-(4-chlorophenyl)-2,3-dihydrothiazole (6e). Yield 88%; m.p.

136.08 (Ar-C), 137.97 (N–C]), 167.51 (C]N–N), 169.44 (N–C] 146–148 ^ꢂC; IR y_max(cm^ꢁ1): 3066 (Ar-H), 2935 (CH₃), 1616 (C]

N); anal. calcd for C₂₇H₂₈BrN₃S (506.50): C, 64.03; H, 5.57; N, N), 1556, 1488 (Ar-C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm:

8.30; found: C, 64.10; H, 5.52; N, 8.34.

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-4-(4-

bromophenyl)-3-(naphthalen-1-yl)-2,3-dihydrothiazole

1.63–1.68 (m, 6H, adamantane –CH₂), 1.73–1.74 (m, 6H, ada-

mantane –CH₂), 1.81 (s, 3H, CH₃–C]N), 1.98 (bs, 3H, ada-

(6b). mantane –CH₂), 4.96 (s, 2H, CH₂), 6.31 (s, 1H, CH–S), 6.98–7.00

Yield 90%; m.p. >300 ^ꢂC; IR y_max(cm^ꢁ1): 3035 (Ar-H), 2941 (m, 2H, Ar-H), 7.18–7.26 (m, 3H, Ar-H), 7.35 (dd, 2H, J ¼ 2.0 Hz,

(CH₃), 1616 (C]N), 1545, 1507 (Ar-C]C); ¹H-NMR (CDCl₃, 400 6.4 Hz, Ar-H), 7.46 (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz, Ar-H); ¹³C NMR

MHz) d ppm: 1.54 (s, 3H, CH₃–C]N), 1.65–1.70 (m, 6H, ada- (DMSO-d₆, 100 MHz) d ppm: 12.48 (CH₃), 28.26 (adamantane-C),

mantane –CH₂), 1.73–1.77 (bs, 6H, adamantane –CH₂), 2.00 (bs, 36.90

(adamantane-C),

39.19

(adamantane-C),

40.67

3H, adamantane –CH₂), 6.18 (s, 1H, CH–S), 6.89 (dd, 2H, J ¼ (adamantane-C), 101.07 (S-CH]), 127.08 (Ar-C), 127.55 (Ar-C),

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128.84 (Ar-C), 129.18 (Ar-C), 130.23 (Ar-C), 130.90 (Ar-C), 134.25 –OCH₂CH₂O–), 6.19 (s, 1H, CH–S), 6.83 (d, 1H, J ¼ 8.4 Hz, Ar-H),

(Ar-C), 137.63 (Ar-C), 139.11 (N–C]), 166.81 (C]N–N), 167.41 6.94–6.97 (m, 2H, Ar-H), 7.03–7.05 (m, 2H, Ar-H), 7.13–7.15 (m,

(N–C]N); anal. calcd for C₂₈H₃₀ClN₃S (476.08): C, 70.64; H, 1H, Ar-H), 7.28–7.30 (m, 2H, Ar-H), 7.35–7.39 (m, 2H, Ar-H); ¹³

C

6.35; N, 8.83; found: C, 70.68; H, 6.30; N, 8.87.

NMR (DMSO-d₆, 100 MHz) d ppm: 14.52 (CH₃), 18.29 (2ꢃCH₃-

(2Z)-2-((1-(adamantan-1-yl)ethylidene)hydrazono)-4-(4-

Ar), 64.32 (O–CH₂), 64.55 (O–CH₂), 100.99 (S-CH]), 115.23 (Ar-

chlorophenyl)-3-(2,6-dimethyl phenyl)-2,3-dihydrothiazole (6f). C), 116.84 (Ar-C), 119.74 (Ar-C), 122.61 (Ar-C), 128.46 (Ar-C),

Yield 82%; m.p. 160–162 C; IR y_max(cm^ꢁ1): 3056 (Ar-H), 2959 128.63 (Ar-C), 128.82 (Ar-C), 130.02 (Ar-C), 131.43 (Ar-C),

ꢂ

(CH₃), 1617 (C]N), 1541, 1493 (Ar-C]C); ¹H-NMR (CDCl₃, 400 132.78 (Ar-C), 136.62 (Ar-C), 139.03 (Ar-C), 143.13 (Ar-C),

MHz) d ppm: 1.65–1.69 (m, 6H, adamantane –CH₂), 1.74 (s, 3H, 144.37 (N–C]), 156.32 (C]N–N), 166.19 (N–C]N); anal.

CH₃–C]N), 1.78–1.79 (bs, 6H, adamantane –CH₂), 2.00 (bs, 3H, calcd for C₂₇H₂₄BrN₃O₂S (534.47): C, 60.68; H, 4.53; N, 7.86;

adamantane –CH₂), 2.13 (s, 6H, 2ꢃCH₃–Ar), 6.08 (s, 1H, CH–S), found: C, 60.74; H, 4.57; N, 7.81.

6.96–7.00 (m, 4H, Ar-H), 7.08–7.10 (m, 3H, Ar-H); ¹³C NMR

(Z)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylidene)

(DMSO-d₆, 100 MHz) d ppm: 12.37 (CH₃), 18.36 (2ꢃCH₃–Ar), hydrazono)-3-(4-uorophenyl)-4-(4-nitrophenyl)-2,3-

28.46

(adamantane-C),

36.98

(adamantane-C),

39.86 dihydrothiazole (7d). Yield 79%; m.p. 224–226 ^ꢂC; IR y_max

(adamantane-C), 40.28 (adamantane-C), 100.37 (S-CH]), (cm^ꢁ1): 3041 (Ar-H), 2942 (CH₃), 1594 (C]N), 1577, 1545 (Ar-

1

128.41 (Ar-C), 128.47 (Ar-C), 128.51 (Ar-C), 129.79 (Ar-C), 134.21 C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.14 (s, 3H, CH₃–

(Ar-C), 136.21 (Ar-C), 136.72 (Ar-C), 138.96 (N–C]), 164.39 (C] C]N), 4.25 (s, 4H, –OCH₂CH₂O–), 6.88 (d, 1H, J ¼ 8.4 Hz, Ar-H),

N–N), 168.82 (N–C]N); anal. calcd for C₂₉H₃₂ClN₃S (490.10): C, 6.93 (s, 1H, CH–S), 7.21–7.30 (m, 4H, Ar-H), 7.36–7.45 (m, 4H,

71.07; H, 6.58; N, 8.57; found: C, 71.01; H, 6.62; N, 8.53.

Ar-H), 8.12 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz, Ar-H); ¹³C NMR (DMSO-

d₆, 100 MHz) d ppm: 14.84 (CH₃), 64.51 (O–CH₂), 64.75 (O–CH₂),

(Z)-4-(4-bromophenyl)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]

dioxin-6-yl)

ethylidene)

hydrazono)-3-phenyl-2,3- 106.12 (S-CH]), 115.03 (Ar-C), 116.19 (Ar-C), 116.42 (Ar-C),

dihydrothiazole (7a). Yield 85%; m.p. 272–274 ^ꢂC; IR y_max117.27 (Ar-C), 119.84 (Ar-C), 124.01 (Ar-C), 129.52 (Ar-C),

(cm^ꢁ1): 3055 (Ar-H), 2975 (CH₃), 1604 (C]N), 1539, 1498 (Ar- 130.98 (Ar-C), 132.03 (Ar-C), 134.28 (Ar-C), 137.33 (Ar-C),

C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm: 2.23 (s, 3H, CH₃–C] 137.91 (Ar-C), 143.54 (Ar-C), 145.02 (Ar-C), 147.24 (N–C]),

N), 4.27 (s, 4H, –OCH₂CH₂O–), 6.16 (s, 1H, CH–S), 6.85 (d, 1H, J 156.45 (C]N–N), 168.29 (N–C]N); anal. calcd for

¼ 8.4 Hz, Ar-H), 6.96–7.00 (m, 2H, Ar-H), 7.22–7.27 (m, 3H, Ar-

C₂₅H₁₉FN₄O₄S (490.51): C, 61.22; H, 3.90; N, 11.42; found: C,

H), 7.30–7.33 (m, 4H, Ar-H), 7.34–7.38 (m, 1H, Ar-H), 7.40 (d, 61.27; H, 3.85; N, 11.45.

1H, J ¼ 2.4 Hz, Ar-H); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm:

(Z)-3-benzyl-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)

14.70 (CH₃), 64.33 (O–CH₂), 64.56 (O–CH₂), 102.25 (S-CH]), ethylidene) hydrazono)-4-(4-nitrophenyl)-2,3-dihydrothiazole

115.33 (Ar-C), 116.85 (Ar-C), 119.86 (Ar-C), 122.37 (Ar-C), 127.40 (7e). Yield 90%; m.p. 202–204 C; IR y_max(cm^ꢁ1): 3051 (Ar-H),

ꢂ

(Ar-C), 128.30 (Ar-C), 128.72 (Ar-C), 129.53 (Ar-C), 131.48 (Ar-C), 2931 (CH₃), 1558 (C]N), 1538, 1497 (Ar-C]C); ¹H-NMR

132.75 (Ar-C), 137.90 (Ar-C), 138.90 (Ar-C), 143.14 (Ar-C), 144.47 (DMSO-d₆, 400 MHz) d ppm: 2.24 (s, 3H, CH₃–C]N), 4.26 (s,

(N–C]), 156.72 (C]N–N), 168.36 (N–C]N); anal. calcd for 4H, –OCH₂CH₂O–), 5.12 (s, 2H, –CH₂–), 6.66 (s, 1H, CH–S), 6.88

C

₂₅H₂₀BrN₃O₂S (506.41): C, 59.29; H, 3.98; N, 8.30; found: C, (d, 1H, J ¼ 8.8 Hz, Ar-H), 7.02 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.19–7.24

59.35; H, 3.95; N, 8.34.

(Z)-3-benzyl-4-(4-bromophenyl)-2-((E)-(1-(2,3-dihydrobenzo

[b][1,4]dioxin-6-yl)ethylidene)hydrazono)-2,3-dihydrothiazole

(m, 4H, Ar-H), 7.31 (s, 1H, Ar-H), 7.67 (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz,

Ar-H), 8.25 (dd, 2H, Ar-H, J ¼ 1.6 Hz, 6.8 Hz); ¹³C NMR (DMSO-

d₆, 100 MHz) d ppm: 14.67 (CH₃), 49.07 (CH₂), 64.50 (O–CH₂),

(7b). Yield 92%; m.p. 284–286 C; IR y_max(cm^ꢁ1): 3055 (Ar-H), 64.74 (O–CH₂), 104.16 (S-CH]), 114.95 (Ar-C), 117.26 (Ar-C),

2969 (CH₃), 1610 (C]N), 1533, 1496 (Ar-C]C); ¹H-NMR 119.72 (Ar-C), 124.31 (Ar-C), 127.17 (Ar-C), 127.75 (Ar-C),

(CDCl₃, 400 MHz) d ppm: 2.30 (s, 3H, CH₃–C]N), 4.28 (s, 4H, 128.97 (Ar-C), 130.20 (Ar-C), 132.26 (Ar-C), 137.23 (Ar-C),

–OCH₂CH₂O–), 5.03 (s, 2H, –CH₂–), 5.95 (s, 1H, CH–S), 6.85 (d, 137.47 (Ar-C), 138.73 (Ar-C), 143.53 (Ar-C), 144.83 (Ar-C),

1H, J ¼ 8.4 Hz, Ar-H), 7.07–7.10 (m, 4H, Ar-H), 7.22–7.26 (m, 3H, 147.92 (N–C]), 155.26 (C]N–N), 168.42 (N–C]N); anal.

Ar-H), 7.37–7.47 (m, 4H, Ar-H); ¹³C NMR (DMSO-d₆, 100 MHz) calcd for C₂₆H₂₂N₄O₄S (486.54): C, 64.18; H, 4.56; N, 11.52;

d ppm: 14.45 (CH₃), 49.30 (CH₂), 64.34 (O–CH₂), 64.56 (O–CH₂), found: C, 64.22; H, 4.50; N, 11.55.

ꢂ

100.75 (S-CH]), 115.23 (Ar-C), 116.86 (Ar-C), 119.76 (Ar-C),

(Z)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylidene)

123.36 (Ar-C), 127.15 (Ar-C), 128.43 (Ar-C), 130.27 (Ar-C), hydrazono)-3-(2,6-dimethylphenyl)-4-(4-nitrophenyl)-2,3-

130.56 (Ar-C), 131.77 (Ar-C), 132.92 (Ar-C), 137.17 (Ar-C), dihydrothiazole (7f). Yield 86%; m.p. 208–210 ^ꢂC; IR y_max

139.49 (Ar-C), 143.16 (Ar-C), 144.34 (Ar-C), 155.69 (N–C]), (cm^ꢁ1): 3008 (Ar-H), 2970 (CH₃), 1590 (C]N). 1557, 1482 (Ar-

1

163.82 (C]N–N), 168.55 (N–C]N); anal. calcd for C₂₆H₂₂

-

C]C); H-NMR (DMSO-d₆, 400 MHz) d ppm: 2.05 (s, 3H, CH₃–

BrN₃O₂S (520.44): C, 60.00; H, 4.26; N, 8.07; found: C, 60.07; H, C]N), 2.12 (s, 6H, 2ꢃCH₃-Ar), 4.25 (s, 4H, –OCH₂CH₂O–), 6.88

4.22; N, 8.12.

(d, 1H, J ¼ 9.2 Hz, Ar-H), 7.01 (s, 1H, CH–S), 7.13–7.21 (m, 3H,

Ar-H), 7.26–7.29 (m, 2H, Ar-H), 7.37 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz,

(Z)-4-(4-bromophenyl)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]

dioxin-6-yl) ethylidene) hydrazono)-3-(2,6-dimethylphenyl)-2,3- Ar-H), 8.08 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz, Ar-H); ¹³C NMR (DMSO-

dihydrothiazole (7c). Yield 81%; m.p. 236–238 ^ꢂC; IR y_maxd₆, 100 MHz) d ppm: 14.63 (CH₃), 18.22 (2ꢃCH₃-Ar), 64.50 (O–

(cm^ꢁ1): 3025 (Ar-H), 2983 (CH₃), 1606 (C]N), 1589, 1483 (Ar- CH₂), 64.73 (O–CH₂), 105.56 (S-CH]), 110.17 (Ar-C), 114.96 (Ar-

C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm: 2.15 (s, 3H, CH₃–C] C), 117.26 (Ar-C), 119.73 (Ar-C), 124.06 (Ar-C), 128.57 (Ar-C),

N), 2.16 (s, 3H, CH₃-Ar), 2.17 (s, 3H, CH₃-Ar), 4.27 (s, 4H, 129.06 (Ar-C), 129.43 (Ar-C), 132.04 (Ar-C), 136.47 (Ar-C),

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136.93 (Ar-C), 138.03 (Ar-C), 143.52 (Ar-C), 144.90 (Ar-C), 147.37 6.66 (s, 1H, CH–S), 7.12–7.21 (m, 4H, Ar-H), 7.29–7.33 (m, 3H,

(N–C]), 155.95 (C]N–N), 166.42 (N–C]N); anal. calcd for Ar-H), 7.38–7.46 (m, 5H, Ar-H), 7.68 (s, 1H, CH]N), 8.27–8.29

C

₂₇H₂₄N₄O₄S (500.57): C, 64.78; H, 4.83; N, 11.19; found: C, (m, 1H, Ar-H), 8.36 (s, 1H, indole CH), 11.51 (s, 1H, NH); ¹³C

64.72; H, 4.85; N, 11.15.

NMR (DMSO-d₆, 100 MHz) d ppm: 102.50 (S-CH]), 112.30 (Ar-

(Z)-4-(4-chlorophenyl)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]

C), 113.01 (Ar-C), 120.91 (Ar-C), 122.05 (Ar-C), 122.52 (Ar-C),

dioxin-6-yl)ethylidene)

hydrazono)-3-phenyl-2,3- 122.95 (Ar-C), 124.96 (Ar-C), 128.18 (Ar-C), 129.15 (Ar-C),

dihydrothiazole (7g). Yield 78%; m.p. 172–174 ^ꢂC; IR y_max129.40 (Ar-C), 130.52 (Ar-C), 128.75 (Ar-C), 130.72 (Ar-C),

(cm^ꢁ1): 3067 (Ar-H), 2931 (CH₃), 1601 (C]N), 1545, 1501 (Ar- 131.69 (Ar-C), 137.57 (Ar-C), 138.24 (Ar-C), 138.79 (N–C]),

C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm: 2.21 (s, 3H, CH₃–C] 149.27 (C]N–N), 167.09 (N–C]N); anal. calcd for C₂₄H₁₇BrN₄S

N), 4.25 (s, 4H, –OCH₂CH₂O–), 6.13 (s, 1H, CH–S), 6.83 (d, 1H, J (473.39): C, 60.89; H, 3.62; N, 11.84; found: C, 60.82; H, 3.68; N,

¼ 8.4 Hz, Ar-H), 7.01–7.03 (m, 2H, Ar-H), 7.13–7.15 (m, 2H, Ar- 11.89.

H), 7.20–7.23 (m, 3H, Ar-H), 7.28–7.36 (m, 3H, Ar-H), 7.39 (d,

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

1H, J ¼ 2.0 Hz, Ar-H); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: bromophenyl)-3-cyclohexyl-2,3-dihydrothiazole (8b). Yield 80%;

14.72 (CH₃), 64.33 (O–CH₂), 64.56 (O–CH₂), 102.19 (S-CH]), m.p. 284–286 ^ꢂC; IR y_max(cm^ꢁ1): 3125 (N–H), 3052 (Ar-H), 1606

115.33 (Ar-C), 116.86 (Ar-C), 119.86 (Ar-C), 127.40 (Ar-C), 128.31 (C]N), 1533, 1489 (Ar-C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm:

(Ar-C), 128.53 (Ar-C), 128.72 (Ar-C), 129.29 (Ar-C), 129.93 (Ar-C), 1.03–1.56 (m, 3H, cyclohexyl), 1.60–1.74 (m, 5H, cyclohexyl),

132.75 (Ar-C), 137.89 (Ar-C), 143.13 (Ar-C), 144.47 (N–C]), 2.58–2.67 (m, 2H, cyclohexyl), 3.60–3.66 (m, 1H, cyclohexyl),

156.69 (C]N–N), 168.40 (N–C]N); anal. calcd for C₂₅H₂₀

-

5.79 (s, 1H, CH–S), 7.14–7.22 (m, 4H, Ar-H), 7.30–7.36 (m, 2H,

ClN₃O₂S (461.96): C, 65.00; H, 4.36; N, 9.10; found: C, 65.04; H, Ar-H), 7.48–7.51 (m, 2H, Ar-H), 8.25 (s, 1H, CH]N), 8.41–8.43

4.31; N, 9.16.

(m, 1H, Ar-H), 8.54 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz)

ppm: 25.09 (cyclohexyl-C), 26.15 (cyclohexyl-C), 29.06

(Z)-4-(4-chlorophenyl)-2-((E)-(1-(2,3-dihydrobenzo[b][1,4]

d

dioxin-6-yl)ethylidene)

hydrazono)-3-(4-uorophenyl)-2,3- (cyclohexyl-C), 59.31 (cyclohexyl-C), 100.37 (S-CH]), 110.96 (Ar-

dihydrothiazole (7h). Yield 81%; m.p. 170–172 ^ꢂC; IR y_maxC), 114.96 (Ar-C), 121.29 (Ar-C), 123.07 (Ar-C), 123.24 (Ar-C),

(cm^ꢁ1): 3050 (Ar-H), 2948 (CH₃), 1596 (C]N), 1560, 1517 (Ar- 125.08 (Ar-C), 127.15 (Ar-C), 130.46 (Ar-C), 130.53 (Ar-C),

C]C); ¹H-NMR (CDCl₃, 400 MHz) d ppm: 2.12 (s, 3H, CH₃–C] 131.86 (Ar-C), 131.96 (Ar-C), 136.88 (Ar-C), 140.21 (N–C]),

N), 4.25 (s, 4H, –OCH₂CH₂O–), 6.13 (s, 1H, CH–S), 6.82 (d, 1H, J 146.94 (C]N–N), 167.77 (N–C]N); anal. calcd for C₂₄H₂₃BrN₄S

¼ 8.4 Hz, Ar-H), 6.96–7.02 (m, 4H, Ar-H), 7.15–7.19 (m, 4H, Ar- (479.44): C, 60.12; H, 4.84; N, 11.69; found: C, 60.17; H, 4.80; N,

H), 7.34 (dd, 1H, J ¼ 2.4 Hz, 8.8 Hz, Ar-H) 7.39 (d, 1H, J ¼ 11.62.

2.0 Hz, Ar-H); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 14.69

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-3-(4-

(CH₃), 64.33 (O–CH₂), 64.56 (O–CH₂), 102.21 (S-CH]), 115.34 uorophenyl)-4-(4-nitrophenyl)-2,3-dihydrothiazole (8c). Yield

(Ar-C), 115.62 (Ar-C), 115.84 (Ar-C), 116.88 (Ar-C), 119.87 (Ar-C), 83%; m.p. 238–240 ^ꢂC; IR y_max(cm^ꢁ1): 3342 (N–H), 3064 (Ar-H),

128.67 (Ar-C), 129.35 (Ar-C), 129.65 (Ar-C), 129.94 (Ar-C), 130.03 1610 (C]N), 1542, 1502 (Ar-C]C); ¹H-NMR (DMSO-d₆, 400

(Ar-C), 132.63 (Ar-C), 143.15 (Ar-C), 144.54 (Ar-C), 156.92 (Ar-C), MHz) d ppm: 6.93 (s, 1H, CH–S), 7.18–7.28 (m, 4H, Ar-H), 7.39–

160.08 (N–C]), 162.54 (C]N–N), 168.33 (N–C]N); anal. calcd 7.48 (m, 5H, CH]N, Ar-H), 7.72 (d, 1H, J ¼ 2.4 Hz, Ar-H), 8.13

for C₂₅H₁₉ClFN₃O₂S (479.95): C, 62.56; H, 3.99; N, 8.76; found: (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz, Ar-H), 8.26–8.28 (m, 1H, Ar-H), 8.39

C, 62.63; H, 3.92; N, 8.84.

(Z)-3-benzyl-4-(4-chlorophenyl)-2-((E)-(1-(2,3-dihydrobenzo

[b][1,4]dioxin-6-yl)ethylidene)hydrazono)-2,3-dihydrothiazole

(s, 1H, indole CH), 11.55 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100

MHz) d ppm: 105.80 (S-CH]), 112.86 (Ar-C), 116.55 (Ar-C),

120.85 (Ar-C), 120.94 (Ar-C), 122.49 (Ar-C), 123.07 (Ar-C),

(7i). Yield 84%; m.p. 150–152 C; IR y_max(cm^ꢁ1): 3012 (Ar-H), 124.01 (Ar-C), 124.87 (Ar-C), 129.49 (Ar-C), 131.04 (Ar-C),

2960 (CH₃), 1602 (C]N), 1578, 1507 (Ar-C]C); ¹H-NMR 131.22 (Ar-C), 134.49 (Ar-C), 137.25 (Ar-C), 137.64 (Ar-C),

(CDCl₃, 400 MHz) d ppm: 2.27 (s, 3H, CH₃–C]N), 4.25 (s, 4H, 138.00 (Ar-C), 147.25 (Ar-C), 149.89 (N–C]), 160.20 (C]N–N),

–OCH₂CH₂O–), 5.00 (s, 2H, –CH₂–), 5.92 (s, 1H, CH–S), 6.82 (d, 166.88 (N–C]N); anal. calcd for C₂₄H₁₆FN₅O₂S (457.48): C,

1H, J ¼ 8.4 Hz, Ar-H), 7.05–7.07 (m, 2H, Ar-H), 7.10–7.12 (m, 2H, 63.01; H, 3.53; N, 15.31; found: C, 63.07; H, 3.48; N, 15.35.

ꢂ

Ar-H),7.19–7.23 (m, 3H, Ar-H), 7.26–7.28 (m, 2H, Ar-H) 7.37 (dd,

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

nitrophenyl)-3-phenyl-2,3-dihydrothiazole (8d). Yield 80%; m.p.

1H, J ¼ 2.0 Hz, 8.4 Hz, Ar-H) 7.40 (d, 1H, J ¼ 2.4 Hz, Ar-H); ¹³

C

NMR (DMSO-d₆, 100 MHz) d ppm: 14.46 (CH₃), 49.28 (CH₂), 296–298 ^ꢂC; IR y_max(cm^ꢁ1): 3297 (N–H), 3041 (Ar-H), 1615 (C]

64.34 (O–CH₂), 64.56 (O–CH₂), 100.74 (S-CH]), 115.23 (Ar-C), N), 1553, 1499 (Ar-C]C); ¹H-NMR (Acetone + DMSO-d₆, 400

116.87 (Ar-C), 119.76 (Ar-C), 127.16 (Ar-C), 127.26 (Ar-C), MHz) d ppm: 6.93 (s, 1H, CH–S), 7.18–7.22 (m, 2H, Ar-H), 7.33–

128.43 (Ar-C), 128.81 (Ar-C), 130.33 (Ar-C), 132.92 (Ar-C), 7.35 (m, 3H, Ar-H), 7.39–7.46 (m, 5H, Ar-H, CH]N), 7.71 (d, 1H,

137.18 (Ar-C), 139.45 (Ar-C), 143.16 (Ar-C), 144.33 (N–C]), J ¼ 2.8 Hz, Ar-H), 8.10 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz, Ar-H), 8.26–

155.67 (C]N–N), 168.58 (N–C]N); anal. calcd for C₂₆H₂₂

-

8.29 (m, 1H, Ar-H), 8.39 (s, 1H, indole CH), 11.54 (s, 1H, NH);

ClN₃O₂S (475.99): C, 65.61; H, 4.66; N, 8.83; found; C, 65.69; H, ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 105.86 (S-CH]), 112.34

4.61; N, 8.87.

(Ar-C), 112.90 (Ar-C), 120.98 (Ar-C), 122.49 (Ar-C), 123.00 (Ar-C),

123.92 (Ar-C), 124.92 (Ar-C), 128.32 (Ar-C), 128.96 (Ar-C), 129.34

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

bromophenyl)-3-phenyl-2,3-dihydrothiazole (8a). Yield 89%; (Ar-C), 129.54 (Ar-C), 130.97 (Ar-C), 137.58 (Ar-C), 137.66 (Ar-C),

m.p. >300 ^ꢂC; IR y_max(cm^ꢁ1): 3224 (N–H), 3050 (Ar-H), 1610 (C] 138.05 (Ar-C), 138.14 (Ar-C), 147.10 (N–C]), 149.73 (C]N–N),

N), 1572, 1497 (Ar-C]C); ¹H-NMR (DMSO-d₆, 400 MHz) d ppm:

RSC Adv., 2021, 11, 17259–17282 | 17279

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166.81 (N–C]N); anal. calcd for C₂₄H₁₇N₅O₂S (439.49): C, 65.59; 1H, indole CH), 11.50 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100

H, 3.90; N, 15.94; found: C, 65.55; H, 3.95; N, 15.90.

MHz) d ppm: 48.54 (CH₂), 101.10 (S-CH]), 112.29 (Ar-C), 113.10

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-3-benzyl-4-

(Ar-C), 120.86 (Ar-C), 122.55 (Ar-C), 122.93 (Ar-C), 124.97 (Ar-C),

(4-nitrophenyl)-2,3-dihydrothiazole (8e). Yield 80%; m.p. 218– 126.56 (Ar-C), 126.81 (Ar-C), 127.57 (Ar-C), 128.95 (Ar-C), 129.19

220 C; IR y_max(cm^ꢁ1): 3228 (N–H), 3032 (Ar-H), 1605 (C]N), (Ar-C), 129.29 (Ar-C), 130.11 (Ar-C), 130.87 (Ar-C), 134.31 (Ar-C),

ꢂ

1

1536, 1491 (Ar-C]C); H-NMR (Acetone + DMSO-d₆, 400 MHz) 137.60 (Ar-C), 139.39 (N–C]), 148.52 (C]N–N), 166.94 (N–C]

d ppm: 5.12 (s, 2H, –CH₂–), 6.65 (s, 1H, CH–S), 7.02 (d, 2H, J ¼ N); anal. calcd for C₂₅H₁₉ClN₄S (442.96): C, 67.79; H, 4.32; N,

6.8 Hz, Ar-H), 7.19–7.26 (m, 5H, Ar-H, CH]N), 7.44–7.46 (m, 12.65; found; C, 67.86; H, 4.36; N, 12.72.

1H, Ar-H), 7.66 (dd, 2H, J ¼ 2.0 Hz, 6.8 Hz, Ar-H), 7.74 (d, 1H, J ¼

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

2.4 Hz, Ar-H), 8.23 (dd, 2H, J ¼ 2.0 Hz, 7.2 Hz, Ar-H), 8.27–8.30 chlorophenyl)-3-(4-uorophenyl)-2,3-dihydrothiazole (8i). Yield

(m, 1H, Ar-H), 8.47 (s, 1H, indole CH), 11.53 (s, 1H, NH); ¹³C 78%; m.p. 256–258 ^ꢂC; IR y_max(cm^ꢁ1): 3444 (N–H), 3029 (Ar-H),

NMR (DMSO-d₆, 100 MHz) d ppm: 48.82 (CH₂), 103.76 (S-CH]), 1607 (C]N), 1561, 1498 (Ar-C]C); ¹H-NMR (Acetone + DMSO-

112.32 (Ar-C), 113.01 (Ar-C), 120.90 (Ar-C), 122.52 (Ar-C), 122.97 d₆, 400 MHz) d ppm: 6.65 (s, 1H, CH–S), 7.17–7.25 (m, 6H, Ar-H),

(Ar-C), 124.28 (Ar-C), 124.95 (Ar-C), 126.90 (Ar-C), 127.68 (Ar-C), 7.33–7.37 (m, 4H, Ar-H, CH]N), 7.45 (dd, 1H, J ¼ 1.6 Hz, 6.8 Hz,

129.01 (Ar-C), 129.99 (Ar-C), 130.66 (Ar-C), 137.37 (Ar-C), 137.57 Ar-H), 7.69 (d, 1H, J ¼ 2.8 Hz, Ar-H), 8.26–8.28 (m, 1H, Ar-H),

(Ar-C), 137.58 (Ar-C), 138.75 (Ar-C), 147.83 (N–C]), 148.94 (C] 8.36 (s, 1H, indole CH), 11.53 (s, 1H, NH); ¹³C NMR (DMSO-

N–N), 166.94 (N–C]N); anal. calcd for C₂₅H₁₉N₅O₂S (453.52): C, d₆, 100 MHz) d ppm: 102.36 (S-CH]), 112.32 (Ar-C), 112.96 (Ar-

66.21; H, 4.22; N, 15.44; found: C, 66.15; H, 4.19; N, 15.48.

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-3-(3-

methoxyphenyl)-4-(4-nitrophenyl)-2,3-dihydrothiazole

C), 116.18 (Ar-C), 116.40 (Ar-C), 120.94 (Ar-C), 122.51 (Ar-C),

122.97 (Ar-C), 124.93 (Ar-C), 128.86 (Ar-C), 130.15 (Ar-C),

(8f). 130.42 (Ar-C), 130.80 (Ar-C), 131.28 (Ar-C), 131.37 (Ar-C),

Yield 76%; m.p. 276–278 C; IR y_max(cm^ꢁ1): 3320 (N–H), 3012 133.52 (Ar-C), 137.56 (Ar-C), 138.62 (N–C]), 149.37 (C]N–N),

ꢂ

1

(Ar-H), 1603 (C]N), 1545, 1496 (Ar-C]C); H-NMR (Acetone + 167.11 (N–C]N); anal. calcd for C₂₄H₁₆ClFN₄S (446.93): C,

DMSO-d₆, 400 MHz) d ppm: 3.71 (s, 3H, OCH₃), 6.82–6.84 (m, 64.50; H, 3.61; N, 12.54; found: C, 64.58; H, 3.58; N, 12.57.

1H, Ar-H), 6.89–6.92 (m, 2H, Ar-H, CH–S), 7.00 (t, 1H, J ¼ 2.0 Hz,

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

Ar-H), 7.18–7.20 (m, 2H, Ar-H), 7.26 (t, 1H, J ¼ 8.4 Hz, Ar-H), chlorophenyl)-3-(2,6-dimethyl phenyl)-2,3-dihydrothiazole (8j).

7.44–7.50 (m, 3H, Ar-H, CH]N), 7.72 (d, 1H, J ¼ 2.8 Hz, Ar- Yield 86%; m.p. 270–272 C; IR y_max(cm^ꢁ1): 3392 (N–H), 3048

ꢂ

1

H), 8.12 (d, 2H, J ¼ 8.8 Hz, Ar-H), 8.26–8.28 (m, 1H, Ar-H), (Ar-H), 1607 (C]N), 1565, 1503 (Ar-C]C); H-NMR (DMSO-d₆,

8.41 (s, 1H, indole CH), 11.55 (s, 1H, NH); ¹³C NMR (DMSO- 400 MHz) d ppm: 2.11 (s, 6H, 2ꢃCH₃-Ar), 6.72 (s, 1H, CH–S),

d₆, 100 MHz) d ppm: 55.80 (OCH₃), 105.82 (S-CH]), 112.35 (Ar- 7.11–7.13 (m, 4H, Ar-H), 7.16–7.20 (m, 3H, Ar-H), 7.29–7.31 (m,

C), 112.90 (Ar-C), 113.88 (Ar-C), 115.09 (Ar-C), 120.98 (Ar-C), 2H, Ar-H, CH]N), 7.44 (d, 1H, J ¼ 6.8 Hz, Ar-H), 7.65 (d, 1H, J ¼

122.49 (Ar-C), 123.00 (Ar-C), 123.94 (Ar-C), 124.92 (Ar-C), 2.8 Hz, Ar-H), 8.25–8.28 (m, 1H, Ar-H), 8.30 (s, 1H, indole CH),

129.24 (Ar-C), 130.19 (Ar-C), 130.98 (Ar-C), 137.58 (Ar-C), 11.50 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 18.25

137.77 (Ar-C), 138.05 (Ar-C), 139.12 (Ar-C), 147.12 (Ar-C), (2ꢃCH₃-Ar), 101.92 (S-CH]), 112.24 (Ar-C), 112.95 (Ar-C),

149.80 (N–C]), 159.95 (C]N–N), 166.73 (N–C]N); anal. 120.87 (Ar-C), 122.47 (Ar-C), 123.04 (Ar-C), 124.89 (Ar-C),

calcd for C₂₅H₁₉N₅O₃S (469.52): C, 63.95; H, 4.08; N, 14.92; 128.87 (Ar-C), 129.24 (Ar-C), 129.46 (Ar-C), 129.88 (Ar-C),

found: C, 63.90; H, 4.12; N, 14.87.

130.59 (Ar-C), 130.64 (Ar-C), 133.72 (Ar-C), 136.69 (Ar-C),

(Z)-2-((E)-((1H-indol-3-yl)methylene)hydrazono)-4-(4-

137.55 (Ar-C), 137.63 (Ar-C), 138.65 (N–C]), 149.01 (C]N–N),

chlorophenyl)-3-phenyl-2,3-dihydrothiazole (8g). Yield 79%; 165.34 (N–C]N); anal. calcd for C₂₆H₂₁ClN₄S (456.99): C, 68.33;

m.p. >300 ^ꢂC; IR y_max(cm^ꢁ1): 3156 (N–H), 3029 (Ar-H), 1604 (C] H, 4.63; N, 12.26; found: C, 68.41; H, 4.66; N, 12.31.

N), 1577, 1506 (Ar-C]C); ¹H-NMR (DMSO-d₆, 400 MHz) d ppm:

6.65 (s, 1H, CH–S), 7.18–7.21 (m, 4H, Ar-H), 7.28–7.32 (m, 5H,

Conﬂicts of interest

Ar-H), 7.37–7.46 (m, 3H, CH]N, Ar-H), 7.68 (d, 1H, J ¼ 2.8 Hz,

Ar-H), 8.27–8.30 (m, 1H, Ar-H), 8.36 (s, 1H, indole CH), 11.52 (s, The authors declare no conict of interest.

1H, NH); ¹³C NMR (DMSO-d₆, 100 MHz) d ppm: 102.47 (S-CH]),

112.31 (Ar-C), 113.00 (Ar-C), 120.93 (Ar-C), 122.53 (Ar-C), 122.96

(Ar-C), 124.95 (Ar-C), 128.18 (Ar-C), 128.78 (Ar-C), 129.15 (Ar-C),

Acknowledgements

129.40 (Ar-C), 130.28 (Ar-C), 130.34 (Ar-C), 130.72 (Ar-C), 133.39 Z. S. is thankful to Higher Education Commission, Islamabad,

(Ar-C), 137.57 (Ar-C), 138.22 (Ar-C), 138.73 (N–C]), 149.25 (C] Pakistan through Project No. NRPU/6975 for nancial support.

N–N), 167.12 (N–C]N); anal. calcd for C₂₄H₁₇ClN₄S (428.94): C,

67.20; H, 3.99; N, 13.06; found: C, 67.27; H, 3.92; N, 13.14.

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Article Doi

Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors

DOI: 10.1039/d1ra01716k

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Article abstract of DOI:10.1039/d1ra01716k

Full text of DOI:10.1039/d1ra01716k

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