INTRODUCTION:

Compound with five membered ring containing one oxygen and two nitrogen atoms is called oxadiazole or according to older literature, furandiazole. Four types of oxadiazoles are known viz. 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-oxadiazole. Amongst these, 1,3,4-oxadiazole is known to be biologically most potent. This is due to presence in-built toxophoric -N=C-O- linkage¹ and well placed electronegative nitrogen and oxygen atoms.

1 2 3 4

1,2,3-oxadiazole

1,2,4-oxadiazole

1,2,5-oxadiazole

1,3,4-oxadiazole

The presence of 1,3,4-oxadiazole heterocyclic structure in diverse types of biologically active compounds is strongly indicative of the profound effects structure exerts on physiological system, and recognition of this is abundantly reflected in efforts to find useful synthetic drugs.

Literature is flooded with reports of a variety of biological activities of various 1,3,4-oxadiazole derivatives. Considerable evidences has been accumulated to demonstrate the efficacy of various 1,3,4-oxadiazole derivatives, including its use as an analgesic², anti-inflammatory², antimicrobial³, antifungal³, antitubercular⁴, anticonvulsant⁵, antidepressant⁵, antimitotic⁶, anticancer⁶ and MAO-inhibitor⁷. The present work is summary of various reports published on biologically active 1,3,4-oxadiazole-2-thiol derivatives in the recent past.

Anti-inflammatory activity

NSAIDs are widely used for the treatment of pain, fever and inflammation particularly arthritis⁸. NSAIDs reduce the inflammation and pain associated with arthritis by blocking the metabolism of arachidonic acid through the inhibition of enzyme cycloxygenase (COX) and thereby reducing the production of prostaglandins⁹. Since, most of the NSAIDs in the market showed greater selectivity for COX-1 than COX-2. The chronic use of NSAIDs, including diclofenac may elicit appreciable GI irritation, bleeding and ulceration. The incidences of clinically significant GI side effects due to NSAIDs are high (30%) and due to this most of the patients abandon NSAID therapy². GI damage from NSAID is generally attributed to two factors. Local irritation by the carboxylic acid moiety, common to most NSAIDs (topical effect) and decreased tissue prostaglandin production, which undermines the physiological role of cytoprotective prostaglandins in maintaining GI health and homeostasis. This adverse effect may be attenuated in presence of an inhibitor of 5-lipoxygenase (5-LO). 1,3,4-oxadiazole containing compounds found to possess anti-inflammatory poperties by the virtue of dual mechanism, i.e. inhibition of both COX and LO and thus can work as a safer alternative for existing NSAIDs.

Bhandari SV et al.¹⁰ has reported S-substituted phenacyl-1,3,4-oxadiazole-2-thiols [6] as novel anti-inflammatory agents showing significant activity in comparison with standard diclofenac sodium. Amongst the synthesized compounds, 6b exhibited most prominent and consistent activity. The histopathological studies showed that, the synthesized compounds not only retained the anti-inflammatory profile of diclofenac sodium but also helped in eliminating the deadlier gastrointestinal toxicities.

R= a:4-NO₂, b:3-OCH₃, c:3,4-OCH₃, d:3,4-Cl₂, e:4-OH, f:3-NO₂, g:4-Br, h:3-OH

Jakubkiene V et al.¹¹ has reported 5-(6-methyl-2-substituted-4-pyrimidinyloxymethyl)-1,3,4-oxadiazole-2-thiones [7] and their 3-morpholinomethyl derivatives [7A] showing good anti-inflammatory activity against carrageenan and bentonite-induced paw edema in rats. Both these derivatives are having morpholine ring as a substituent on the 2^nd position of pyrimidine in compound [7] and on the 3^rd position of oxadiazole ring in compound [7A]. In the evaluation study, these compounds showed similar anti-inflammatory activity in bentonite test (decreased oedema 27.3%), but found less active in carrageenan test (decreased oedema 17.8%). It was also observed that, introduction of benzylamino group into 2^nd position of pyrimidine ring is unfavorable for anti-inflammatory effect. The synthesized compounds expressed higher anti-inflammatory activity were evaluated for their acute toxicity indicated that, these compounds possessed less toxicity compared to standard acetylsalicylic acid.

R= a:-SCH₂, b:-NCH₂C₂H₅, c:-N(CH₃)₂, d: pyrolidine, e: piperidine, f: morpholine

Manjunatha K et al.⁹ has investigated few new 1,3,4-oxadiazole derivatives [8-9] in search of novel anti-inflammatory agents. In the experimental results, compound [8] containing 4-ethoxycarbonylpiperidin-1-ylmethyl and morpholin-4-ylmethyl substitutions showed good activity. Compound [9] having 4-chlorophenylpiperazin-1-ylmethyl group as a substitution showed the greatest activity (76.63%) compared with standard diclofenac sodium. It was also observed that, Mannich bases having 4-ethoxycarbonylpiperidin-1-ylmethyl,4nitrophenylpiperazin-4-ylmethyl and 4-fluorophenylpiperazin-4-ylmethyl substitutions on oxadiazole ring showed better activity (73.92%, 75.14% and 75.38%) than the standard drug. The highest activity (74.65%) was recorded of Mannich base having 3-chlorophenylpiperazin-4-yl-methyl substitution. When this substitution was replaced by 4-methoxyphenylpiperazin-4-ylmethyl,2-

ethoxyphenylpiperadin-1-ylmethyl, 4-nitrophenylpiperazin-4-ylmethyl, 4-ethoxycarbonylpiperidin-1-ylmethyl and morpholin-4-ylmethyl groups, decrease in activity was seen. It was also noticed that, compounds having 4-chlorophenylpiperazin-4-ylmethyl and 4-fluorophenylpiperazin-4-ylmethyl substituents exhibited good activity, with 71.09%, 68.71% inhibition of inflammation respectively

8 9

R=CH₃,H; R1=CH₂CH(CH₃); X=CHCOOEt,O,NH,N-CH₃; R2=4-OCH₃,4-Cl, 4-NO₂, 4-F, 2-OC₂H₅

Burbuliene MM et al.¹² has reported novel series of 5-[(2-di-substituted amino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones [10] exhibiting better anti-inflammatory activity than standard acetylsalicylic acid in carrageenan test and in bentonite test. The activity observed was found similar to the standard ibuprofen. The derivative containing morpholinyl substitution on the 2^nd position of pyrimidine ring, reported most potent anti-inflammatory agent. In other set of compounds, introduction of various substituents on S- or N 3-positions of 3H-1,3,4-oxadiazole-2-thiones effectively changed the anti-inflammatory activity. S-alkylation of 5-[(2-di-substitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-2,3-dihydro-1,3,4-oxadiazole-2-thiones reported decrease in the activity. S-methyl derivative bearing piperidine moiety on the 2^nd position of pyrimidine ring, exhibited best anti-inflammatory activity amongst the tested compounds. The introduction of aminomethyl group on 3H-1,3,4-oxadiazole ring reduced anti-inflammatory activity. Only compound containing and piperidine ring was found more active in compared with the corresponding 3H-1,3,4-oxadiazole-2-thione. Along with this, all the tested compounds were found less toxic than the reference ibuprofen.

NR₁R₂=Pyrrolidine, Piperidine, Morpholine; NR₃R₄=N(CH₃)₂ Pyrrolidine, Morpholine; R₅=CH₃,C₆H₅

Gilani SJ et al.¹³ has evaluated the anti-inflammatory activity of 5-pyridine-1,3,4-oxadiazole-2-thione [13]. The experimental results have shown that, 2-mercapto group present on the 2^nd position of oxadiazole ring exhibited moderate activity, but from the observations, it was concluded that 1,3,4-oxadiazole derivatives of isoniazide might afford a safer alternative to isoniazide for the treatment of inflammatory disease, pain and hepatotoxicity caused by acetyl hydrazine, a metabolite of isoniazide.

Biju CR et al.¹⁴ has reported series of S-benzoyl-5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol derivatives [14] active against carrageenan induced rat paw edema method. From the experimental observations, 1,3,4- oxadiazole analogues, 14a-c were found to exhibit good anti-inflammatory activity. Acute toxicity studies also showed that these analogues are safe with low toxicity. So, these derivatives may be considered as future leads for anti-inflammatory drug discovery.

R=a:4-OCH₃-C₆H₄-; b:4-OH-C₆H₄-; c:4-NO₂-C₆H₄-COCl

Chilumuru NR et al.¹⁵ has investigated 5-(2-(2-(arylidene amino) oxazole-5-yl-amino) benzoxazole-5-yl)-3-((dialkylamino)methyl)-1,3,4-oxadiazole-2(3H)thiones [15] for the search of possible anti-inflammatory drugs. The pharmacological evaluation studies showed that, compound [15b] possessing good activity with 83.22% inhibition, compounds [15a, 15c] exhibited 79.87% inhibition of inflammation, whereas compound [15d] resulted in 78.61% inhibition in a carrageenan induced paw edema rat model compared to the standard drug diclofenac sodium.

a=RR1=CH₃;Ar=4-N-(CH₃)₂C₆H₅;b=RR1=CH₃;Ar=C₆H₅;c=RR1=(CH₂CH₃)₂; Ar=4-Cl-C₆H₅;d=RR1=(CH₂CH₃)₂; Ar=Veratralyl

Abd alla MSM et al.¹⁶ has reported 1,2-dihydro-4-(3,4-dimethylphenyl)-2-[(5-methylthio)-1,3,4-oxadiazole-2-yl)]phthalazine [16] derivative showing good inhibition of inflammation in carrageenin induced rat paw edema test compared with standard indomethacin. This may be due to the presence of oxadiazole thione ring.

Chandra T et al.¹⁷ has discovered novel 1-(2’4’-disubstituted acridin-9-yl)-3-(5’-pyridin-4-yl)-(1,3,4-oxadiazole-2-yl-thiomethyl)-pyrazole-5-one [17] as potent anti-inflammatory and analgesic agents. The experimental results showed that, chloro group substituted at 2^nd and 4^th positions of the acridine ring resulted in potent compound compared to other substituted acridines.

a:R1= Cl, R2= H; b:R1= OMe, R2= H; c: R1= Br, R2= H; d:R1= OMe, R2= Cl, e:R1=R2=Cl

Antimicrobial

Over the past several years the emergence of pathogens resistant to nearly all the classes of antimicrobials has become a serious public health concern. In general, bacteria have genetic ability to transmit and acquire resistance to drugs. Since past two decades, there has been evidences of significant increase in systemic fungal infections in man. Due to this, design and development of a broad spectrum antifungal agent is the urgent need of today. In the recent past, several researchers have paid their attention to 1,3,4-oxadiazole nucleus containing compounds as these found good therapeutic potential against many pathogens.

Khanum SA et al.¹⁸ has observed the good antimicrobial activity of series of 5-(2-aroylaryloxy) methyl-1, 3,4-oxadiazole-2-(3H) thiones [18]. Many of the synthesized compounds showed significant antimicrobial activity against S. aureus, C. albicans, C. Krusei, C. parapsilosis, T. paradoxa, E. Coli, B. subtilis and P. aerugenosa. Compounds with methyl and methoxy substitutions in ring A and B exhibited good inhibitory activity compared to reference compound against all the strains.

a:R=R3=H,R1=CH₃,R2=Cl;b:R=R2=R3=H,R1=Cl;c:R1=R2=R3=H,R=Br;d:R=R2=H,R1=R3=CH₃

Bayrak H et al.¹⁹ has compared antimicrobial activities of 4-[5-(ethylthio)-1,3,4-oxadiazole-2-yl] pyridine [19], 3-[(4-methylpiperazin-1-yl) methyl]-5-pyridin-4-yl-1,3,4-oxadiazole-2(3H)-thione [20] and 3-{[(2-morpholin-4-ylethyl) amino] methyl}-5-pyridin-4-yl-1,3,4-oxadiazole-2(3H)-thione [21] with ampicillin and fluconazole. Amongst the tested compounds, the S-ethylated derivative [19] has shown good antibacterial activity against E. coli, Y. pseudotuberculosis, P. aerugenosa, E. faecalis, S. aureus whereas Mannich bases showed moderate activity towards various test organisms.

Sahin G et al.²⁰ has identified compound 5-(1/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione [22], significantly active antimicrobial, against S. aureus, E. coli, P. aeruginosa, C. albicans and C. parapsilosis. The activity observed, was attributed to the bulkier group present on the oxadiazole ring and presence of toxophoric unit in oxadiazole nucleus.

a: 1-Naphthyl; b: 2-Naphthyl

El-Emam AA et al.²¹ has reported series of 5-(1-adamatyl)-3-arylaminomethyl-1,3,4-oxadiazole-2-thiones [23] and 5-(1-adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-oxadiazoline-2-thiones [24] active against gram-positive, gram-negative bacteria and fungi; C. albicans. The biological evaluation results has shown that, compounds 24a and 24b possessed excellent activity against gram-positive bacteria, good activity against the gram-negative bacteria species and moderate activity against C. albicans. Amongst the arylaminomethyl derivatives prepared, 4-chlorophenyl, 2-trifluroethylphenyl, 2,5-diflurophenyl substituted compounds were registered most active

R=a:4-F; b:4-Cl; c:2-CF₃; d:2,5-F₂

R=a:CH₃; b:4-FC₆H₄

Al-Omar MA et al.²² has observed good antimicrobial activity of 5-(2-thienyl)-1,3,4-oxadiazoles derivatives [25-27]. The pathological examinations have observed that, N-Mannich derivatives 25a-e, 26a, b and 27a-f possessing good antibacterial activity are due to the substitution of aminomethyl group. The arylaminomethyl-1,3,4-oxadiazoline-2-thiones 25a-e were reported active against both the gram-positive and gram-negative bacterial strains. The piperazine derivatives 27a-f with methyl, phenyl, 4-fluorophenyl and 2-trifluoromethylphenyl substitutions were reported highly active against the gram-positive bacteria and to lesser extent against the gram-negative bacteria. In the detail study it was concluded that, replacement of the methyl or aryl group on compound 27a and 27d respectively with a 4-benzyl and 2-trifluromethylbenzyl moieties to form compounds 27e and 27f respectively dramatically reduced the antimicrobial activity indicating that smaller groups are preferable.

R=25a:2-F,b:4-F,c:4-Cl,d:2-CF_3,e:3-CF₃;

R=26a:CH₃,b:C₆H₅CH₂;

R=27a:CH_3,b:C₆H_5,c:4-FC₆H₄,d:2-CF₃C₆H_4,e:C₆H₅CH₂

Jha KK et al.²³ has successfully conducted biological evaluation of 5-(substituted)-2-thio-1,3,4-oxadiazole [28] against E. coli, S. epidermidis and S. aureus bacterial strains using disk diffusion method. The experimental results has shown that, aryl group with less electronegative substituent resulted in the highest activity.

R=a:C₈H₈O₂, b:C₅H₅N

Mayekar AN et al.²⁴ has investigated the N-Mannich bases substituted 1,3,4-oxadiazole derivatives bearing bromonaphthalene moiety [29] for their antimicrobial potential. The experimental results concluded that, Mannich bases 29a-e are having remarkable activity against all tested microorganisms. This may be attributed to the association of pharmacologically active morpholine, 4-methylpiperazine, 2-fluorophenyl, 4-chlorophenyl and 2-methylphenyl groups with oxadiazole ring. S-methylation 29b caused decrease in activity against most of the strains.

29a

R'= primary/secondary amine

29b

R''= CH₃, C₂H₅, substituted benzyl

a:C₄H₉NO; b:C₅H₁₂N₂; c:2-F-C₆H₄N; d:3-(4-Cl-C₆H₆N); e:C₇H₉N

Salimon J et al.²⁵ has noticed very good antibacterial activity of 2-[5-thiol-1,3,4-oxadiaxol-2-yl]-9(10H)-acridone [30] against some common bacterial species. The antimicrobial evaluation results revealed that, activity is mainly because of the presence of the versatile pharmacophore 1,3,4-oxadiazole-2-thione consisting of well in-built toxophoric unit and acridone nucleus which increases the lipophilic character of the molecule, to facilitate the crossing of the compound through the biological membrane of the microorganisms and inhibit their growth.

Mallikarjuna BP et al.²⁶ reported 5-(4-isopropylthiazole-2-yl)-1,3,4-oxadiazoles-2-thiol [31] active against gram-positive bacteria S. aureus, S. feacalis, B. subtilis, gram-negative bacteria K. penumoniae, E. coli, P. aeruginosa and fungal species C. tropicalis, S. cervisiae, A. niger. A pathological study has concluded that, compound 31 is active at MIC 8 and 31.25 μg/mL compared to standard ciprofloxacin and fluconazole against all tested microorganisms except a moderate potency with S. aureus.

Maslat AO et al.²⁷ has successfully evaluated antibacterial and antifungal activities of 5,5’-dimercapto-bis-[1,3,4-oxadiazol-2-yl]propane [32a], 5,5’-dimercapto-bis-[1,3,4-oxadiazol-2-yl]butane [32b], 5,5’-dimercapto-bis-[1,3,4-oxadiazol-2-yl]octane [32c] and 5,5’-dibenzylthio-bis-[1,3,4-oxadiazol-2-yl]butane [33] against S. aureus, B. subtilis, P. aeruginosa and C. albicans . It is noted that, the addition of benzyl group as a substituent enhanced the antifungal activity and length of alkane present between two hetero rings played an important role in exhibiting antimicrobial activity.

a:(n=3); b:(n=4); c:(n=8)

n=4

Rajasekaran S et al.²⁸ has reported novel 5-pyridyl-2-[(N-substituted-phenyl)-thioacetamido]-1,3,4-oxadizole [34] derivatives as good antibacterial agents. Compounds were assayed by agar cup plate method using B. subtilis, S. aureus, E. coli and P. aeuroginosa employing ampicillin as a standard drug. In the experimental observations, compound possessing a dichloro substitution on the phenyl ring has shown promising antibacterial activity against gram-positive organisms while the compound possessing a single chloro substitution on the phenyl ring has shown good antibacterial activity against gram-negative pathogens. In the detailed study, the compound possessing a chloro substitution on the phenyl ring has inhibited the DPPH radical at lower concentration and was found comparatively better than the other compounds of the series.

R=2-CH₃; 3-CH₃; 4-CH₃; 2-Cl; 4-Cl; 4-Br; 2,6-Cl

Gudasi K et al.²⁹ has identified antibacterial and antifungal activity of the ligand, transition metal salts and the corresponding complexes with a new tridentate ligand, 5-[6-(5-mercapto-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazole-2-thiol [35] assayed against two bacteria, E. coli, B. cirroflagellosus and two fungi, A. niger and C. albicans, using cup plate method. The pathobiological examination results were compared against the standards norfloxacin and griseofulvin. The ligand was observed weakly active against the bacteria and inactive against the fungi used. The Cu(II) and Zn(II) complexes of the same ligand were found to be more active, while the Mn(II), Co(II) and Ni(II) complexes were seen moderately active.

M= Mn(II), CO(II), Ni(II), Cu(II), Zn(II)

Joshi SD et al.³⁰ has found that, 5-(4-pyrrol-1-yl phenyl)-1,3,4-oxadiazole-2-thiol [36] is active as an antibacterial at MIC value of 8 µg/mL against B. subtilis. Due to better activity against tested microorganisms, this compound has been selected for further development and studies to acquire information about SAR.

Ramaprasad GC et al.³¹ has noticed that, 5-[substituted-(1,1’-biphenyl)-3-yl]-1,3,4-oxadiazole-(3H)-thiones [37] and its S-alkyl derivatives are active as antimicrobials against S. aureus, P. aeruginosa, E. coli, B. subtilis. The experimental results have shown that, the fluoro substituted compound 37d is the most active in the series.

a:R1=5'-F, 2'-OMe, R2=-(CH₂)₃COOMe;

b:R1=2'-OMe, R2=-(CH₂)₃COOMe;

c:R1=3'-Cl, R2=-(CH₂)₃COOMe; d:R1=2'-F, R2=-(CH₂)₄F

Raval JP et al.³² has reported new oxoethylthio-1,3,4-oxadiazole derivatives [38] active against known species of bacteria. The biological evaluation report has shown that, compound 38b and 38h with 2-Cl and 2-CH₃ substitution respectively on the phenyl nucleus exhibited moderate to good activity against gram-negative organisms and compounds 38c and 38d with 3-Cl and 4-Cl substitution respectively on the phenyl nucleus exhibited moderate to good activity against gram-positive pathogens only. Compound 38j with 4-CH₃ substitution showed moderate to good activity against S. aureus and S. paratyphi. While the compound 38k with 4-C₅H₅N has shown remarkable antibacterial activity against all tested organisms.

R= a:H; b:2-Cl; c:3-Cl; d:4-Cl; e:2-NO₂; f:3-NO₂; g:4-NO₂; h:2-CH₃; i:3-CH₃; j:4-CH₃; k:2-C₅H₅N; l:2-OH

liang-zhong XU et al.³³ has registered better antifungal activity of 5-[(1H-1,2,4-triazol-1-yl) methyl]-1,3,4-oxadiazole-2-thiols derivatives [39] against C. arachidicola and P. pircola at concentration 50µg/mL, compared to the commercial agent. As far as substituent (R) is concern, compounds 39d and 39h with 4-CH₃C₆H₄COCH₂ and 2,5-Cl₂C₆H₄COCH₂ substitutions respectively inhibit the fungal growth to maximum.

R=a:C₆H₅COCH₂; b:4-ClC₆H₄COCH₂; c:4-FC₆H₄COCH₂; d:4-MeC₆H₄COCH₂; e:4-MeOC₆H₄COCH₂; f:2,4-Cl₂C₆H₃COCH₂; g:2,4-F₂C₆H₃COCH₂; h:2,5-Cl₂C₆H₃COCH₂; i:3,4-Cl₂C₆H₃COCH₂; j:2-F-4-CH₃C₆H₃COCH₂; k:2-F-5-CH₃C₆H₃COCH₂; l:(CH₃)₃CCOCH₂; m:C₆H₅CH₂; n:2,4-Cl₂C₆H₃CH₂; o:4-(CH₃)₃CC₆H₄CH₂; p:2-Cl-pyridine-CH₂; q:CH₂=CHCH₂; r:C₄H₉

Li Y et al.³⁴ has observed that, (E)-α-(methoxyimino)-benzene acetate derivatives containing 1,3,4-oxadiazole nucleus

[40] were profoundly active against pathogenic species R. solani, B. Cinereapers, G. Zeae, P. Piricola and B. mayclis. The experimental data has revealed that, out of the synthesized compounds, fluorinated compounds such as 40j and 40l exhibited higher activity than that of standard Kresoxim-methyl. The results also demonstrated the introduction of 1,3,4-oxadiazole rings to the strobilurin fungicides might improve their fungicidal activities.

R= a:H; b:4-OMe; c:4-C₆H₅-CH₂O; d:3-Cl; e:2,3-Cl₂; f:2,4-Cl₂; g:2,5-Cl₂; h:2,4-Cl₂-5-F; i:2-F; j:4-F; k:2-F-4-Br; l:2,3-F₂; m:4-CF₃; n:2-I; o:4-NO₂.

Liu F et al.³⁵ has discovered that, 2-substituted sulfinyl 5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole-2-thiol derivatives[41] are possessing good fungicidal properties when tested against fungal strains G. zeae, F. oxysporum, C. mandshurica using poison plate technique. In the biological evaluation, compound 41a displayed good inhibitory activity and wide spectrum of bioactivity. Using the mycelia growth rate method, the mechanism of action of 41a against S. sclerotiorum was studied. From the experimental evaluation data collected, it was concluded that, 41a provides high inhibitory effect on the growth of most of the fungi with the EC₅₀ values ranging from 13.9-63.9µgm/mL.

R=a: -CH₂CH₃-C₆H₅; b: -CH2CH3-C6H4-3-OMe; c: -CH₂CH₃-C₆H₄-3-F; d: -CH2CH3-C6H4-2-Cl; e: -CH₂CH₃-C5H3N-Cl; f: -CH₂COOCH₂CH₃; g: -CH₂CH₃-C₆H₄-2-F;

h: -CH₂CH₃-C₆H₄-2-OMe

Chen CJ et al.³⁶ has identified that, 5-(3,4,5-trimethoxyphenyl)-2-sulphonyl-1,3,4-oxadiazole derivatives [42] are possessing higher antifungal activities against the few pathogenic fungi in-vitro. In the activity evaluation results, compound 42b and 42c showed higher inhibitory effects on the growth of G. zeae, P. grisea, C. mandshurica, C. gloeosporioides, B. cinerea, S. sclerotiorum, T. oryzae, P. infestans, R. solani and F. oxysporum, with EC₅₀ values ranging from 2.9µgm/mL-93.3µgm/mL, compared to standard hymexazole.

R= a: CH₃CH₂CO-CO-CH₂-; b: H₃C-; c: CH₃CH₂-; d: 4-MeO-C₆H₄-CH₂-

Xu W et al.³⁷ has observed that, novel sulfone derivatives containing 1,3,4-oxadiazole moieties are promising antifungal agents active against F. oxysporum, C. mandshurica, R. solani, T. cucumeris, S. sclerotiorum, C. gloeosporioides, P. infestans, B. cinere bolia. Amongst them, few compounds such as 43a showed very good activity with EC₅₀ values ranging from 5.21µg/mL to 79.2µg/mL, and compounds 43a, 43b and 43c exhibited the superior activity over the commercial fungicide hymexazol. In particular, compounds 43b, 43c, 43d, and 43e reported to have prominent activity against B. cinerea, with EC₅₀ values of 5.21µg/mL, 8.25µg/mL, 8.03µg/mL, 21.00µg/mL respectively. The results demonstrated that compound 43b can be used as possible lead for the development of potential antifungal agent.

R=a: 2,3,4-F₃-C₆H₂-; b:2-F-C₆H₄-; c:2,6-F₂-C₆H₃-; d:2,6-Cl₂-C₆H₃; i: 2-Br-C₆H₄

Chen Q et al.³⁸ has successfully designed a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives bearing 1,3,4-oxadiazole moiety [44] in search of a potential candidate as antifungal agent. Their antifungal activities against R. solani were evaluated in-vitro. At the end of the study it was noticed that, compound 44d [R₁=CH₃CH₂(CH₃)CH, R=X=H, EC50=6.57 mg/mL] from the series exhibiting the highest antifungal activity, compared with carbendazim (EC50=7.62mg/mL), trimethyl derivatives bearing p-chlorobenzyl group also displaying higher activities than the corresponding dimethyl derivatives, however, trimethyl derivatives bearing p-nitrobenzyl group reported lower activities than the corresponding dimethyl derivatives, indicating that, the effect of α-methyl group in the bridge is very complex. Amongst the monomethyl derivatives containing a substituted benzyl group, electron-withdrawing group on 4^th position of the benzyl ring resulted in higher activity. It was also noted that, the electrostatic and steric properties played an important role in the antifungal activity. According to the SAR analysis, R₁, R and X substitutions for the best antifungal activity are sec-butyl, CH₃ and CH₃, respectively.

a:R=X=H,R₁=4-NO₂C₆H₄CH₂;b:R=X=H,R₁=4-BrC₆H₄CH₂; c:R=X=H,R₁=4-FC₆H₄CH₂; d:R=X=H,R₁=CH₃CH₂(CH₃)CH;

e:R=X=H,R₁=4-CH₃C₆H₄CH₂;f:R=X=H,R₁=4-OCH₃C₆H₄CH₂;g:R=X=H,R₁=4-FC₆H₄CH₂; h:R=X=H,R₁=CH₃CH₂(CH₃)CH.

Antimycobacterial activity

The exponential increase in TB cases has been greatest in areas with high prevalence of HIV infections. The emergence of multiple drug-resistant (MDR) TB has focused the attention of the scientific community throughout the world to develop new and powerful antitubercular drug^39,
40. In this context, many research groups have successfully designed and investigated various 1,3,4-oxadiazole derivatives. These researchers has got paramount of success and as a result of which, many 1,3,4-oxadiazole derivatives nowadays are in the various phases of clinical trials.

Shaharyar M et al.⁴¹ has successfully designed a series of Mannich bases, 3-[2-furyl(4-{4-[2-furyl(5-substituted-henyl-2-thioxo-2,3-dihydro-1,3,4-oxadiazole-yl)methlamino]phenylsulfonyl} aniline)methyl]-5-( substituted phenyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones [45a-g] and 5-(substituted phenyl)-3-phenyl{4-[4-phenyl(5-substituted phenyl-2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)methylamino-phenylsulphonyl]aniline}methyl-2,3-dihydro-1,3,4-oxadiazole-2-thiones [45h-n] exhibiting anti-tubercular activity against isoniazide resistant M. tuberculosis. Among the compounds synthesized, 45d and 45f were observed most active agents with activity more than 10-fold than isoniazide against INH resistant M. tuberculosis. It was also concluded that, this class of compound certainly hold great promise for the discovery of novel antimycobacterial agents.

a:R1=C₆H₅, R2= Furfuryl-; b:4-NO₂C₆H₅,R2= Furfuryl-; c:C₆H₅-NH-C₆H₅, R2= Furfuryl-; d:β-C₁₀H₇-OCH₂, R2= Furfuryl-; e:α-C₁₀H₇-OCH₂, R2= Furfuryl-; f:C₆H₅-OCH₂, R2= Furfuryl-; g:C₆H₅CH₂; R2= Furfuryl-; h:R1=C₆H₅, R2=Phenyl-; i:4-NO₂C₆H₅, R2=Phenyl-; j:C₆H₅-NH-C₆H₅, R2=Phenyl-; k:β-C₁₀H₇-OCH₂, R2=Phenyl-; l:α-C₁₀H₇-OCH₂, R2=Phenyl-; m:C₆H₅-OCH₂, R2=Phenyl-; n:C₆H₅CH₂; R2=Phenyl-

Macaev F et al.⁴² has viewed novel 5-aryl-2-thio-1,3,4-oxadiazole derivatives [46], good anti-mycobacterial agents active against M. tuberculosis. Rifampicin was used as a standard in the assay. Compounds 46a-c and 46e-o were recorded active against the said pathogenic species in evaluations studies. The best antituberculosis activity was noted for compound 46p (56%) followed by compound 46b (37%). It seems that bulky substitution on the 2^nd position of benzene ring is not favorable for the activity. A significant increase in activity (up to 90%, 96%, and 98%) was observed in the series of derivatives with monoethanolamine residues substituted on the aromatic ring and mercapto-group substituted with 4-fluorophenacyl, phenacyl, allyl, and 2,4-dichlorophenacyl groups.

a: R1=SCN; R2=H; R3=CH₃CH=CH₂; b: R1= SCN; R2=H; R3=Me

Macaev F et al.⁴³ has successfully worked to develop a series of 5-aryl-2-thio-1,3,4-oxadiazoles [47-48] in search of a better antitubercular agent effective against M. tuberculosis. Rifampicin was used as the control standard in the assay. In the assay, the maximum activity among the 3,4,5-trimethoxy analogues was observed for compound 48b. It was also noticed that, when number of methoxy groups decreased to one on the aromatic ring of 5-aryl-1,3,4-oxadiazole, activity was reduced to minimum.

47a: R1=Cl, R2=R4=H, R3=Cl; R1=R4= H, R2=R3=OMe; c: R1=OH, R2=R3=H, R4=Me; d: R1=Br, R2=R3= H, R4=Me; e: R1=H, R2=R3=OMe, R4=Me; f: R1=H, R2=R3=OMe, R4=CH₂Py;

48a: R1=R2=R3=R4=R5=H; R6=F b: R1=H, R2=R3=OMe, R4=R5=H; R6=Me

Anticancer Activity

Cancer is the major cause of deaths of human beings around the world. WHO projected twelve million deaths by cancer with existing therapeutics by 2030? Taking into consideration the existing cancer therapies, chemotherapy has turned out to be one of the most significant treatments in cancer management. The natural product based drugs, are extensively used in the treatment of wide variety of cancers because of their efficacy. However, they suffer from hematopoietic and neurologic toxicities. This alarms the need of newer chemical entity with effective therapeutic window. In search of this, many research groups looking positively towards 1,3,4-oxadiazole nucleus containing compounds to serve the purpose.

Aboraia AS et al.⁴⁴ has investigated a series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives [49] for their utility as an anticancer agent. In primary assay, few compounds displayed high anticancer activity, which were selected for full anticancer screening against a 60-cell panel assay. The experimental results have shown that, all the selected compounds were observed non-selective broad spectrum and possessing promising activity against all cancer cell lines. Compound 49b and 49c were proved to be the most promising derivatives with less toxicity.

R= a: -NH-C₆H₄(2-Cl), b: -NH-C₆H₄(3-Cl), c: -NH-C₆H₄(2-Cl), d: -NH-C₆H₄(2-COOH), e: -NH-C₆H₄(4-COOH), f: -NH-C₆H₄(4-COCH₃), g: -NH-C₆H₃(2-OH-4-COOH)

Zheng QZ et al.⁴⁵ has carried out biological evaluation of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety [50] in search of potential antitumor agents active against gastric cell SGC-7901. The evaluation results have shown that, compounds with electron donating groups on the ortho position of benzene ring (eg. 50a, 50c, 50e) displaying less inhibitory activity than those with the same groups on the para position (eg. 50b, 50d, 50f). The substitution pattern on benzene ring demonstrated that para substituted halogen derivatives (eg. 50h, 50j) are more active than ortho substituted halogen derivatives (eg. 50g, 50i). Antiproliferative assay results also indicated that compound 50k and 50l exhibited the most potent activity against gastric cancer cell SGC-7901.

R= a:2-Me-C₆H₄-; b:4-Me-C₆H₄-; c:2-MeO-C₆H₄-; d:4-MeO-C₆H₄-; e:2-EtO-C₆H₄-; f:4-EtO-C₆H₄-; g:2-F-C₆H₄-; h:4-F-C₆H₄-; i:2-Cl-C₆H₄-; j:4-Cl-C₆H₄-; k:2-OH-4-MeO-C₆H₃-;

Gudipati R et al.⁴⁶ has reported newer series of 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}-5 or 7-di-substituted indolin-2-one derivatives [51] active as growth inhibitor of the test HeLa, IMR-32 and MCF-7 cancer cell lines. The experimental results have reported that, 5-halo substituted compound are the most potent anticancer agent in the series. The results also indicated that, C-5 substituted derivatives may be considered as useful leads for anticancer drug development in the future.

R1= a: H, b: F, c: Cl, d: Br, e: CH₃, f: NO₂, g: COOH, h: H, i: H, j: H, k: H, l: H; R2= a: H, b: H, c: H, d: H, e: H, f: H, g: H, h:Cl, i: NO₂, j: CH₃, k:COOH, l: COOCH₃

Abu-Zaied MA et al.⁴⁷ has effectively discovered novel 5-(3-isobutyl-1-phenyl-1H-pyrazole-4-yl) 3-substituted-1,3,4-oxadiazole-2-thiol derivatives [52] having cyclic and acyclic carbohydrate residues through S-glycosidic bond formation active against 2-cell lines, MCF-7 (breast) and HEPG2 (liver). In the assay results, compounds 52a and 52b were reported as very good anticancer agents. None of the tested compounds have shown any toxicity in the doses ranging from 50 to 500 mg/kg of the animal body weight. The lethal doses (LD₅₀) of tested compounds were identified >500 mg/kg body weight.

a b

Anticonvulsant Activity

Despite the development of several novel anticonvulsants, the treatment of epilepsy remains still inadequate. About one third of patients do not respond well to currently available treatments, even if multiple drugs with complementary activities are used. So, there is urgent need to develop drugs which are more potent and at the same time better tolerated than existing drugs. Designing of 1,3,4-oxadiazole derivatives could be the answer for the problem.

Zarghi A et al.⁴⁸ has developed new 2-alkylthio-5-(2-benzylthiophenyl}-1,3,4-oxadiazole [53] derivatives, useful for the treatment of convulsions. In this series of 2-alkylthio oxadiazoles, only compound 53a was reported to have a weak anticonvulsant activity. Compound possessing a small alkylthio group at C-2 of the 1,3,4-oxadiazole ring have shown good anticonvulsant activity in the MES model but mild activity against PTZ induced convulsions.

R= a: SCH3; b: SC₂H₅; c: SBz

Almasirad A et al.⁴⁹ has studied various 5-[2-(2-fluorophenoxy) phenyl]-1,3,4-oxadiazole-2(3H)-thiones [54] for the search of novel anticonvulsant agent. Anticonvulsant effects of these compounds have been determined using pentylenetetrazole (PTZ) induced lethal convulsion and maximal electroshock (MES) tests. Flumazenil, a benzodiazepine antagonist was used as standard. In the experimental observations, compound 54 with SH substituent has shown mild effects in PTZ and MES tests.

R=SH

Miscellaneous

Abou-Seri SM et al.⁵⁰ has successfully recorded the anticancer and potential epidermal growth factor receptor tyrosine kinase inhibitory properties of novel 2,4’-bis mercapto 1,3,4-oxadiazole substituted diphenylamines derivatives [55]. Almost all the compounds have registered good both activities. Compound with free SH group resulted in decrease in activity. This may be attributed to the polar nature of the group to reduce the cellular penetration. The elaboration of the 5-mercapto with alkyl group resulted in two fold increase in activity while substitution with more lipophilic benzyl moiety produced the most active antiproliferative agent.

R=a:C₂H₅; b:CH₂C₅H₅; c:C₃H₅

Wael A et al.⁵¹ has reported antiviral evaluation of new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their acyclic nucleoside analogues [56] against HIV by using HIV replicon cells. In the anti-HIV assay results, substituted sugar hydrazone, compound 56a, observed the most active with MIC of 1.33µg/cm³. This indicated the importance of the free hydroxyl galactopentitolyl moiety, as the activity was reduced when this group was O-acetylated 57a or replaced by the xylotetritolyl moiety 56b.

R=a: D-galactopentitolyl

b: D-xylotetritolyl

R=a: 1,2,3,4,5-penta-O-acetyl-D-galactopentitolyl.

b:1,2,3,4-tetra-O-acetyl-D-xylotetritolyl.

Sun Y et al.⁵² has reported the biological evaluation of various novel human stem/progenitor cells proliferation activators, 4-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)-phenyl)thiosemicarbazide [58] derivatives. The effects of the small molecules were represented by cell viability (%). Compound 58a (Stemazole) and 58g (bromine-substituted Stemazole) promoted stem cell proliferation in-vitro.

a: R1=R2= H; b: R1=H, R2=CH₃; c: R1=H, R2= -CH₂Ph; d: R1=H, R2=Ph; e: R1=H, R2=p-Cl-Ph; f: R1=H, R2=p-OMe-Ph; g: R1=Br, R2=H

Khan KM et al.⁵³ has reported the non competitive nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors, 1,3,4-oxadiazole-2(3H)-thiones [59]. Compounds 59a-e were found active with IC₅₀ values in the range of 3.83-9.60µM. From the observation data collected, it was noticed that, the presence of oxygen or sulfur in five-membered heterocyclic ring, as well as the substitution of various groups at C-5 played an important role in the activity against the snake venom NPP1. It was also discovered that the presence of hydrogen at C-3 of the heterocyclic ring contributed favorably in the inhibitory activity.

R= a: C₆H₅OSi(CH₃)₂C(CH₃)₂, b: (CH₂)₃, c=CH₃, d: C₆H₅OCH₂C₆H₅, e: 4-OH-C₆H₅

CONCLUSION:

This paper has reviewed the researches undertaken by the various research groups on 1,3,4-oxadiazole-2-thione compounds in recent past. It is evident that, in this area, tremendous work is progressed in the last decade or so. The large numbers of derivatives consisting of this nucleus are successfully designed and found useful against number of disorders.

The most important development of this class is mainly occurred in the successful designing of novel antibacterial, antifungal, anti-tubercular and anti-inflammatory agents.

The good antimicrobial properties of 1,3,4-oxadiazole-2-thione derivatives are attributed to the well in-built toxophoric (-N=C-O-) unit, while better anti-inflammatory potential of this type is due to the fact that, these compounds inhibit both cyclooxygenase and lipooxygenase enzymatic systems.

From the literature data studied, the basic pharmacophoric requirements for the antimicrobial and anti-inflammatory activities are observed as under.

The bulkier substitutions required on the oxadiazole ring for the antimicrobial activity is explained that, because of this,

compound can cross the biological membrane of the microorganisms easily and inhibit their further growth. The substitution pattern on the oxadiazole nucleus shown for the anti-inflammatory action is mainly responsible for its binding to the active sites available on cyclooxygenases and lipooxygenases.

As scientific community all over the world has created lots of interest in the research and development of 1,3,4-oxadiazole ring containing drugs due to its advantages over existing chemicals, in near future more 1,3,4-oxadiazole-2-thione nucleus containing clinically useful candidates with good curative effects, low toxicity and superior pharmacokinetics properties will be launched as novel molecules that could be used in clinic. And, it is all possible that, this will be proved remarkable contribution in prevention of diseases and protection of human’s health with utmost priorities.

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Received on 15.03.2012 Modified on 30.03.2012

Asian J. Research Chem. 5(6): June, 2012; Page 794-807