Schiff bases and Bicyclic derivatives comprising 1, 3, 4-thiadiazole moiety- A Review on their Pharmacological activities

 

Sherin A. Hameed1, Joyamma Varkey2, P. Jayasekhar3

1College of Pharmaceutical Sciences, Govt. Medical College, Thiruvananthapuram-695011

2College of Pharmaceutical Sciences, T.D Medical College, Alappuzha-688005

3College of Pharmacy, National University of Science and Technology, Muscat, Oman

*Corresponding Author E-mail: sherinirshad@gmail.com

 

ABSTRACT:

1, 3, 4-thiadiazole is a well-known heterocyclic nucleus which form an integral feature of various natural products and medicinal agents. It has enormous biological potential due to their privileged structure and is able to undergo various chemical reactions which make researcher more comfortable in drug designing. The stability of thiadiazole nucleus has inspired medicinal chemist to carryout various structural variations in the ring. This review highlights the pharmacological activity of recently synthesized Schiff bases and fused ring systems comprising1,3,4- thiadiazole moiety.

 

KEYWORDS: 1, 3, 4-thiadiazole, Schiff bases, triazolothiadiazole, antimicrobial activity, anticonvulsant activity, antioxidant activity, anticancer activity, antidiabetic activity, antidepressant activity.

 

 


INTRODUCTION:

Thiadiazole is a significant heterocyclic nucleus with two carbon atoms, two hydrogens, two nitrogens and one sulphur. The molecular structural formula is C2H2N2S. They occur in four isomeric forms viz 1,2,3-thiadiazole; 1,2,5-thiadiazole and 1,3,4-thiadiazole 1

 

1,2,3-thiadiazole                                     1,2,5-thiadiazole

 

1,2,4-thiadiazole                                      1,3,4-thiadiazole

 

In recent decades, researchers mainly focus on thiadiazole moiety because of its versatile biological activities. Strong aromaticity of the ring system gives greater stability and possesses low toxicity for higher vertebrates. Thiadiazole moieties with different substituents proved to have great advancement in biological activities like analgesic, antimicrobial, anti-inflammatory, anti-tubercular, anticonvulsant, antioxidant antidiabetic and anticancer activities.

 

Literature survey indicated that more research has been carried out on 1,3,4-thiadiazole than all other isomers. Many drugs containing 1,3,4-thiadiazole nucleus such as acetazolamide, methazolamide, megazol are commercially available drugs.

 

Acetazolamide

 

Methimazole

 

Megazol

 

Schiff bases are compound with general structure R1R2C=NR3. They can be formed when any primary amine reacts with an aldehyde or ketone under specific conditions. It is a nitrogen analog of an aldehyde or ketone in which the carbonyl group (C=O) has been replaced by an imine or azomethine group.

 

R1, R2 &/R3= alkyl /aryl

 

General structure of Schiff base:

Schiff bases exhibit a wide range of biological activities and are extensively used organic compound. Thiadiazole moiety fused with other heterocyclic nuclei like imidazole, triazole, pyramidine to form bicyclic compounds which also have broad range of biological applications.

 

The present review covers advances made in pharmacological activities of Schiff bases and bicyclic derivatives of 1,3,4- thiadiazole in last two decades. The biological activities of 1,3,4-thiadiazole can be classified into following catagories.

·         Anti-bacterial and antifungal

·         Antitubercular

·         Antioxidant

·         Anti-inflammatory and analgesic

·         Anticonvulsant

·         Antidiabetic

·         Anticancer

 

Antibacterial and antifungal activity:

Development of resistance to the latest range of antibiotics increased the need of research for better and least toxic antimicrobial agents. Extensive studies were done on 1,3,4-thiadiazole derivatives for their antimicrobial activities. Shavkar Sharada Devi et al 2 synthesized a series of 1,3,4-thiadiazole derivatives bearing Schiff bases and were screened for antibacterial (Bacillus subtilis, Escherichia coli), and antifungal (Penicillium chrysogenum) activity by agar cup plate method. Compounds 1a and 1b showed potent activity compared to ofloxacin as the reference antibacterial drug and 2a showed equipotent activity compared to fluconazole as reference standard for antifungal activity.

 

1a

 

1b

 

2a

Krishnakant et al 3 worked on a series of substituted thiadiazole Schiff bases. Among them compound 3a showed maximum zone of inhibition while 3b, a minimum activity for gram-positive E.coli bacteria. Compound 3a also showed significant activity against gram- negative S.aureus bacteria.

 

3a

 

3b

 

Schiff bases of 2-amino-5-aryl-1,3,4-thiadiazole derivatives were prepared by the reaction of thiosemicarbazide, sodium acetate and aromatic aldehyde. Alok Pandey et al 4 reported these compounds for their significant antibacterial activity against S. aureus and E. coli. The compounds 4a, 4b, 4c, 4d showed good antibacterial activity against S. aureus. Except 4a all other compounds along with 4e showed good activity against E.coli.

 

4(a-e)

Compound 

4a

4b

4c

4d

4e

R

-OCH3

-NO2

-N(CH3)2

-N(CH3)2

-OH

R1

-OH

-OH

-OH

-NO2

-OH

 

5-(p-substituted phenyl)-N-(3-(5-nitrofur-2-yl) allylidine)-1,3,4-thiadiazole-2-amines were prepared by Salih et al 5. The preliminary screening results showed the association of the chemical structure and antimicrobial activity. SAR studies were performed and reported that the presence of halogens and nitro substituents on the aromatic ring has increased the activity than others. This may be due to the increase in the lipophilic character of the molecule facilitating passage through biological membrane of microorganism. Compound 5a showed significantly high activity as antifungal agent and maximum activity against gram negative E.faecalis, while compound 5b against gram positive S.aureus.

 

5a

5b

 

Imidazo [2,1b] [1,3,4]-thadiazole derivatives were synthesized, characterized and screened for antifungal and antibacterial activities by Alegaon and Alagawadi 6. Among them 6a, 6b, 6c and 6d exhibited significant activity. Enhanced antimicrobial activity of these compounds were due to introduction of 4-bromophenyl and 4-chlorophenyl group at 6th position of imidazo [2, 1-b] [1,3,4-] thiadiazole.

 

6(a-d)

Compound

R

X

6a

4-Br

O

6b

4-Cl

O

6c

4-Br

S

6d

4-Cl

S

 

Rakesh et al7 synthesized and screened biphenyl imidazo [2,1-b] [1,3,4]-thiadiazole derivatives for antibacterial activity against strains of E.coli, P.aeruginosa and B. subtilis and antifungal activity against C. albicans, Saccharomyces cervisiae and Aspergillus niger by in vitro methods. Compound 7(a-h) and 8(a-h) showed good antibacterial activity as compared to drug ampicillin. But antifungal screening reported moderate activity as compared to Amphotericin B.

 

7 & 8 (a-h)

Compound

R1

Compound

R1

R=H for 7(a-h)

a

H

e

4’NH2

b

4’Cl

f

2’4’-diOH

 

R=F for 8(a-h)

c

4’F

g

4’Br

d

2’,4’-diCl

h

2’OH

 

Rohit Bhatia and Amandeep Kaur 8 reported the antimicrobial activity of their newly synthesized imidazothiadiazole derivatives 9(a-j). Among them 9(a-c) exhibited good result for antimicrobial activity giving a conclusion that halogen (-Cl, -F, -Br) substituted thiadiazole were found to possess greater activity than –CH3 and –OCH substituted derivatives.

 

9 (a-j)

 

Compound

R

Compound

R

a

-Cl

e

-NO2

b

-Br

f

-OCH3

c

-F

g

-NH2

d

-CH3

h

-OH

 

Yousif et al9 synthesized novel tetra Schiff bases of 1,3,4-thiadiazole moiety. All compounds were screened for antibacterial and antifungal activities by paper disc diffusion method. The minimum inhibitory concentration (MICs) of the compounds were determined by agar streak dilution. Compound 10 i.e (1,2,4,5-tetra(5-(4-nitrobenzylideneamino) 1,3,4-thiadiazole-2-yl) benzene found to be potent antibacterial and antifungal agent when compared to Ciprofloxacin and ketoconazole. SAR studies revealed that the presence of strong electron withdrawing substituent, two nitro groups in the benzylideneamino moiety of the 1,3,4-thiadiazole accounts for its better activity.

 

10(a-h)

Compound

R

Compound

R

a

H

e

p-NO2

b

p-CH3

f

p-Br

c

p-OH

g

p-OCH3

d

o-OH

h

p-Cl

 

Amandeep Kaur et al 10 reported the synthesis of novel heterocyclic derivatives comprising imidazole and 1,3,4-thiadiazole containing biphenyl moiety. Compounds 11(a-h) and 12(a-h) were screened for antibacterial activity against various strains of E. coli, P. aeruginosa and B. subtilis and antifungal activity against C. albicans, S. cerevisiae and Aspergillus niger. All the compounds showed good antibacterial activity against various strains of bacteria comparable to standard Ampicillin. They have moderate activity against Candida albicans and Aspergillus niger but no activity against Saccharomyces cerevisiae as compared to Amphotericin B.

 

 

11 a-h

 

12 a-h

Compound

R

Compound

R

a

H

e

-4’NH2

b

-4’Cl

f

-2’,4’diOH

c

-4’F

g

-4’Br

d

-2’,4’diCl

h

-2’OH

 

Some new binary and spiro heterocyclic thiadiazolo[4,3-b] [1,3,4] thiadiazole ring systems were synthesized by Mona E Ibrahim et al 11. The synthesized compounds were screened for antibacterial activity against gram positive Bacillus subtilis and gram negative Escherichia coli as well as for antifungal activity against Candida albicans. Compounds 13a,13b and 13c exhibited moderate activity against gram positive but compound 13a have excellent activity against E. coli. None of the compound showed antifungal activity.

 

 

13a

 

13b

 

13c

 

Antitubercular activity:

Syed et al 12 recently synthesized and reported the antitubercular activity of some novel imidazothiadiazole derivatives. Among all the tested derivatives, compounds 14a1, 14a2, 14a3,14c1 and 14d1 gave good antitubercular activity. Methoxy / nitrosubstitution at 4th position of phenyl ring at 4th position of thiazole and nitro or chloro or methoxy substitution on 4th position of phenyl ring of condensed imidazo[2,1-b][1,3,4]-thiadiazole is responsible for increased antitubercular action of these compounds. Good antifungal activities were also exhibited by them.

 

14 (a1-6) to (d1-6)

Series

R1

Code

R2

a

 

b

 

c

d

p-NO2

 

p-Br

 

p-OCH3

p-Cl

1

p-Cl

2

p-Br

3

p-CH3

4

p-OCH3

5

p-NO2

6

m-NO2

 

Kolavi et al13 elucidated the antitubercular and antimicrobial activity of a series of 2,6-disubstituted and 2,5,6 trisubstituted imidazo[2,1-b] [1,3,4]-thiadiazole. Compound 15a and 15b showed highest inhibitory activity (100%)

 

15a

15b

 

Anti-inflammatory and Analgesic activity:

Alok Pandey et al 4 also evaluated their Schiff bases for the anti-inflammatory and analgesic activity. Compounds 16a, 16b, 16c and 16e were shown significant analgesic activity against swiss albino mice and compounds 16b, 16c, 16f and 16j showed good anti-inflammatory activity against wister albino rats.

 

16(a-e)

 

Compound

R1

R2

Compound

R1

R2

a

-OCH3

-OH

f

-OCH3

-NO2

b

-OH

-OH

g

-OH

-NO2

c

-Cl

-OH

h

-Cl

-NO2

d

-NO2

-OH

j

-NO2

-NO2

e

-N(CH3)2

-OH

k

-N(CH3)2

-NO2

 

Anticonvulsant activity:

Ahmed et al 14 made extensive study on Schiff bases of 1,3,4 thiadiazole prepared by them for anticonvulsant activity in vivo. anticonvulsant activity was evaluated by MES test method. Compound 17a (parent compound) showed 50% protection towards MES induced hind limb extension and showed soon recovery. Chlorobenzylated imines 19c showed 100% protection towards MES induced hind limb extension with fast recovery with no neurotoxicity while benzylated imines 18 b showed 83.3% protection with slow recovery.

  

 

17a

 

18(a-e)

 

19(a-e)

 

Compound

R

Compound

R

a

-2Cl

d

-4NO2

b

-4Cl

e

-4F

c

-2NO2

 

Pooja mullick et al 15 screened a series of thiadiazole –thiazolidinone derivatives for anticonvulsant activity by MES model followed by neurotoxicity screening. Compounds 20a,20e,20j and 21j are short acting anticonvulsant. Unsubstituted compounds 20a and compounds with electronegative substituents 20e,20j &21j were found to be more potent than those with electron releasing groups.

 

 

20(a-l)

 

21(a-l)

 

Com

pound

R

Com

pound

R

Compound

R

a

-H

e

-4Cl

i

-4NO2

b

-2CH3

f

-2Br

j

-2,4-diCl

c

-4CH3

g

-4Br

k

-2OH

d

2-Cl

h

-3NO2

l

4-OCH3

 

Antioxidant activity:

Shavkar Sharada Devi et al 2 worked on imine linked 1,3,4-thiadiazoles and the synthesized molecules were screened for antioxidant activity. compound 22f showed potent antioxidant activity with IC50 value of 0.09µg/ml. Compounds 22a and 22c showed good and 22g with moderate activity.

 

 

22(a-h)

Compound

Ar

Compound

Ar

a

e

b

f

c

g

d

h

 

Kahlan 16 prepared 2,5-di (N-substituted benzylidine amino)-1,3,4-thiadiazole 23 (a-j) and their antioxidant activity were tested. Among them 23e showed maximum activity. Presence of hydroxyl group at para position contributed to antioxidant activity.

 

 

23(a-j)

 

Compound

a

b

c

d

e

R

H

-4Cl

-4Br

-4OCH3

-4OH

f

g

h

i

j

-3Cl

-3Br

-OCH3

-3NO2

-3OH

 

 

Ramesh et al 17 synthesized two series of 1,3,4-thiadiazole and were subjected to antioxidant activity evaluation by various methods like Nitric oxide scavenging method and hydrogen peroxide scavenging assay. On comparing IC50 values, compounds 24e and 25e in nitric oxide radical scavenging method and compound 24a, 24d, 25a and 25d in hydrogen peroxide method exhibited potent antioxidant activity.

 

 

 

For 24 (a-e) Ar =-4-ClC6H4

For 25(a-e) Ar= 3-pyridyl

 

Compound

a

b

c

d

e

R

4-OH

4-N(CH3)2

4-OCH3

3,4,5-(OCH3)3

4-NO2

 

B. Mathew et al 18 designed and synthesized a series of imines of 2-amino-5thio-1, 3, 4-thiadiazole linked to benzimidazole chalcones. All compounds were screened for antioxidant activity by DPPH method. All of them showed good activity. Compounds 26e, 26a, 26b showed a good free radical scavenging activity with an IC50 of 0.32, 0.39 and 0.42mM respectively. The SH group of 1,3,4-thiadiazole group can donate hydrogen atom and exist in a radical form which can remove free radicals.

 

 

26(a-f)

Code

a

b

c

d

e

f

R

H

4-Cl

-4-OCH3

4-N(CH3)2

-3-NO2

2-OH

 

Anticancer activity:

M.N. Noolvi et al19 made excellent study on imidazothiadiazole moiety for their anticancer activity. A series of 2,5,6 trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives were synthesized. Among them, 5-bromo-6-(4-chlorophenyl)-2-cyclopropyl imidazo[2,1-b][1,3,4]-thiadiazole  27 found to have maximum activity with selectivity towards leukemic cancer cell lines.

 

27

Kumar et al 20 performed QSAR studies on a series of imidazo[2,1-b]1,3,4-thidiazole derivatives as murine leukemia cell inhibitors (compound 28 and 29). They have generated model with good correlation between murine leukemic cell inhibitory activity and thermodynamic, electronic and steric properties of the derivatives.

 

 

28

 

29

 

Rashid et al 21 rationally designed and synthesized four series of benzimidazole derivatives based on heterocyclic core of bendamustine. All compound was subjected to in vitro anticancer screening against 60 human cell lines obtained from 9 clinically isolated cancer types. Among them compound 30 exhibited activities against leukemia and melanoma cell lines.

 

 

30

Chariot et al 22 performed extensive study on anticancer activity of 3,6 disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. Twenty different derivatives were synthesized and screened against nine well established human cancer cell lines (4 ovarian, 2 breast, 1 prostate cancer, 1-epidermoid carcinoma and 1 leukemia). Among these compounds 31a and 31b exhibited a very potent cytostatic and cytotoxic effect against all tested cell line in vitro. They showed better or equal activity on comparison with three well established anticancer drugs on current cancer chemotherapy.

 

 

31

Code

R

31a

4-ClC6H4

31b

C6H5-CH=CH

 

Baburajeev et al23 reported the synthesis and biological evaluation of a library of triazolo-thiadiazole derivative as a potent inhibitor of human heparinase. Among the tested derivatives, compound 32 was found to exert an antiproliferative effect with IC50 value 11.9 and 8.3µM against LLC (Mouse Lewis Lung Carcinoma) and HepG2 (Human Hepatocellular Carcinoma). Structure activity relationship revealed that phenolic and iodine substituents on the triazolothiadiazole moiety and exo-conjugation of the core structure enhanced the cytotoxic effect, while hydrophobic substituents were ineffective.

 

 

32

Amandeep Kaur et al 10 also reported the anticancer activity of biphenyl imidazo[2,1-b] [1,3,4] thiadizole derivatives. Primary in vitro one dose   anticancer assay was performed in 60 cell panels representing leukemia melanoma and cancers of lung, colon, brain, breast, ovary, kidney and prostate. Compound 33b and 33d exhibited moderate anticancer activity

 

 

33

 

Compound

R

Compound

R

a

H

e

-4’NH2

b

-4’Cl

f

-2’,4’diOH

c

-4’F

g

-4’Br

d

-2’,4’diCl

h

-2’OH

 

Antidiabetic activity:

Datar PA and Deokule TA 24 designed and synthesized imine derivatives of 1,3,4-thiadiazole molecule and subjected to antidiabetic activity by in vivo and in vitro methods. Compound 34a was found to show potent antidiabetic activity in alloxan induced diabetic rat model. Molecular docking studies of synthesized molecules revealed that synthetic derivatives and target proteins were actively involved in binding and had significant correlation with biological activity.

 

 

34a

 

Merlin et al 25 designed and synthesized a series of 1, 3 4- thiadiazole substituted 2-methyl benzimidazole derivatives. The derivatives were screened for anti-diabetic and anti-inflammatory activity by in vitro methods. The compound 35 exhibited significant antidiabetic and anti-inflammatory activities.

 

 

35

 

CONCLUSION:

1,3,4-thiadiazole is a unique template that is associated with several biological activities. The broad and potent activity of thiadiazole and their derivatives have made them a pharmaceutically significant scaffold. Schiff base compounds and fused ring systems comprising 1,3,4-thiadiazole ring reviewed here, enhances expectations in improving potency with least toxicity with the help of analysis on structure activity relationship with their mechanism of action. Further research is required for developing better drugs with improved potency and lesser toxicity.

 

ACKNOWLEDGEMENT:

The author is very grateful to the Institute and the Department for the support.

 

CONFLICT OF INTEREST:

We declare that we have no conflict of interest.

 

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Received on 22.08.2019         Accepted on 20.09.2019

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2019; 9(4):299-306.

DOI: 10.5958/2231-5691.2019.00047.9