INTRODUCTION:

Heterocyclic chemistry has been a major field of interest for medicinal chemists, searching for compounds such as acridines, pyrazolones, pyrazoles, imidazoles, oxazoles, oxazolidines, pyridines and thiazolines; with promising pharmacological activity. Among various heterocyclic ring systems, 1,2,4-oxadiazoles have been studied extensively in past 20 years, owing to their use in medicines, pesticides and material science¹. The five membered heterocyclic ring system containing oxygen and two nitrogen atoms at position 1, 2 and 4 respectively, acts as aromatic linker. The presence of furan type oxygen atoms and two pyridine type nitrogens makes 1,2,4-oxadiazole ring electron poor azole. As substituent, its effects however, are much similar to that of nitro or cyano group and the electron withdrawing effect of 1,2,4-oxadiazole ring is more prominently exerted via C₅ than C₃².

1,2,4-Oxadiazole serves as an important pharmacophore for ligand binding in Computer aided drug discovery programs. It also act as bioisostere for esters, amides, carbamates and hydroxamic esters, due to their property to form hydrogen bonds and act as aromatic linker for substituents³.

In addition to its use as peptidomimetic, 1,2,4-oxadiazoles also acts as ligands for benzodiazepine receptor and dopamine receptor (D4), agonists of muscarinic receptor, sphingosine-1-phosphate receptor, antagonists against 5-HT₃ receptor, inhibitors of tyrosine kinase, monoamine oxidase, aldose reductase, MIF and bell-tryptase. Also, they have been evaluated as antitumor agents, anti-inflammatory agents, antirhino viral agents, dilators of coronary artery, in treatment of Alzheimer’s disease, antibacterial activity against gram-positive and gram-negative bacteria and antifungal activity⁴. Natural compounds Phidianidines A and B and Quisqualic acid, isolated from Phidiana militaris, a sea slug, and seeds of Quisqualis indica, respectively have also been found to contain 1,2,4-oxadiazole ring. Phidianidines A and B have been found to be selective inhibitor of dopamine transporter DAT and partial agonist of μ opoid receptor. Similarly, Quisqualic acid shows strong agonistic activity on AMRA receptors and Metabotropic Glutamate receptors⁵.

METHODS OF SYNTHESIS

The general method of preparation of 1,2,4-oxadiazoles involves any of the two methods:

1. 1,3-dipolar cycloaddition of nitriles to nitrile oxides

2. Cyclization of Amidoxime derivatives

For both the synthesis routes, the starting material employed is nitrile which is then converted to amidoxime by reaction with hydroxylamine hydrochloride, and further reacts with carboxylic acids or their derivatives to give the oxadiazole ring. The substituents at C₃ and C₅, can be varied by selecting the synthetic route as nitrile precursor is linked at C₅ via cycloaddition with nitrile oxides, while at C₃ via Amidoxime cyclization.

Polothi et al. synthesized 1,2,4-oxadiazole linked with 1,3,4-oxadiazole. Reaction involves coupling of 4-cyano-benzohydrazide with 3,4,5-trimethoxybenzoyl chloride in the presence of dry pyridine and refluxing for 30min, thereby producing an intermediate which was again refluxed for 1 hr with phosphorus oxychloride, yielding 1,3,4-oxadiazole. The oxadiazole on reaction with hydroxylamine hydrochloride and aqueous sodium hydroxide, was converted to Amidoxime and was then cyclized to desired 1,2,4-oxadiazole by refluxing with substituted aromatic acids in the presence of dioxane or pyridine ^6,7.

Karad et al. reported the synthesis of morpholinoquinoline derivatitives of 1,2,4-oxadiazole. The reaction involves conversion of 2-morpholinoquinoline-3-carbonitriles to Amidoxime in the presence of hydroxylamine hydrochloride and sodium carbonate, and was cyclized to desired 1,2,4-oxadiazole by one-pot reaction with benzoic and in the presence of ethyl-(N’,N’’-dimethylamino)-propyl-carbodiimide hydrochloride (EDC.HCl) followed by refluxing for 3 hrs in the presence of sodium acetate and ethanol (Scheme-1)⁸.

Scheme-1

Cao et al. reported the synthesis of substituted phenyl piperidinyl-1,2,4-oxadiazole derivated using cyanides. Substituted N-(3-(4-phenylpiperazin-1-yl)propyl) cyanamide was converted to N-hydroxy guanidine intermediate in the presence of hydroxylamine hydrochloride, diisopropylethylamine (DIPEA), which on reaction with substituted benzoic acids in was converted to the 1,2,4-oxadiazole in the presence of HATU, DIPEA and DCM at room temperature overnight, followed by refluxing in DCE for 5 hrs⁹.

Mohammadi-Khanaposhtani et al. prepared acridone substituted 1,2,4-oxadiazoles by acylation of substituted benzamidoximes yielding acylamidoximes, which was then refluxed in toluene and was converted to 1,2,4-oxadiazole nucleus. The compound on reaction with substituted acridone in the presence of potassium-tert-butoxide and DMSO underwent S_N2 reaction and was converted to the desired product (Scheme-2)¹⁰.

Scheme-2

Yoshimura et al. reported the synthesis of 3-aryl-5-aryl-1,2,4-oxadiazoles in one-pot reaction using nitriles and nitriles oxides in excess of solvent, and hydroxy(aryl)iodonium (IBA-OTf). The reagent was prepared by using 2-iodobenzoic acid, trifluoromethanesulfonic acid (TfOH) and m-chloroperoxybenzoic acid (m-CPBA) as oxidant¹¹.

Outirite et al. prepared 3, 5-diaryl-1,2,4-oxadiazoles using microwave irradiation. Aromatic nitrile was subjected to microwave irradiation in one-pot reaction, in the presence of hydroxylamine hydrochloride and sodium carbonate in ethylene glycol and water (3:1), yielding symmetrically substituted 1,2,4-oxadiazoles¹².

Fortuna et al. reported the synthesis of substituted 1,2,4- oxadiazole having similar structure to Linezolid, by replacing morpholine ring with 3-methyl-1,2,4-oxadiazol-5-yl. In order to prepare the desired compound, acetamidoxime was converted to fluoroarylated 1,2,4-oxadiazoles by reaction with mono- or di-fluorobenzoyl chlorides, which underwent SN_Ar on reaction with allyl amine and then on reaction with di-(t-butyl)-dicarbonate followed by iodocyclocarbamation yielded oxazolidinones with a side chain that could be modified as required (Scheme-3)¹³.

Scheme: 3

Neda et al. synthesized 1-[4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl]pyrrolidine-2,5-dione and 1-[4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl]1H-pyrrole-2,5-dione, in two steps, starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)aniline, which was synthesized from tert-butylamidoxime and 4-aminobenzoic acid¹⁴.

Ubaradka et al. synthesized chromeno oxadiazoles using microwave reactor. O-Hydroxybenzaldehyde was coupled with malononitrile in the presence of ethanolic triethylamine to give 2-iminochroman-3-carbonitrile, which was then converted to 2-aminochroman-3-carbonitrile in the presence of ethanolic sodium borohydride. The carbonitrile was converted to amidoxime and then to chromeno oxadiazole under microwave irradiation^15,16.

Jadhav et al reported the synthesis of 3-phenyl-1,2,4-oxadiazole analogs. Reaction involves coupling of 4-nitro benzonitrile with hydroxylamine hydrochloride to give N’-hydroxy-4-nitrobenzamidine, which is then converted to ethyl-3-(4-nitrophenyl)-1,2,4-oxadiazole-5-carboxylate by refluxing with ethyl chloroxalate in pyridine. 3-aryl-1,2,4-oxadiazole-5-carboxylate thus formed, on coupling with _L-valine methyl ester hydrochloride gives (S)-methyl-3-methyl-2-(3-(4-nitrophenyl)-1,2,4-oxadiazole-5-carboxamido)butanoate. The nitro group in compound so formed is reduced to its amine, and is followed by coupling with substituted phenyl isocyanates gives ureas, methy ester group is then deprotected by alkaline hydrolysis to give 3-phenyl-1,2,4-oxadiazoles¹⁷.

Kumar et al. reported solvent free synthesis of 1,2,4-oxadiazoles using four component reaction of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes and malononitrile in a molar ratio of 1:2:1 and in the presence of solid sodium ethoxide to give quantitative yields of a mixture of diastereomeric forms of 4(H)-pyrans. The diastereomeric mixture could not be separated via column chromatography but identified via NMR. The 4(H)-pyrans and nitrile oxide were then made to under go 1,3-dipolar cycloaddition to give the diastereomeric mixture of 1,2,4-oxadiazoles which could be separated using petroleum ether and ethyl acetate as eluent in column chromatography¹⁸.

Bretanha et al. used ultrasound irradiation to prepare substituted-1,2,4-oxadiazoles. Trichloroacetoamidoxime and substituted benzoyl chlorides were irradiated with ultrasound for 15 min, with ethyl acetate as solvent yielding the desired product (Scheme-4)¹⁹.

Scheme-4

Srivastava et al. established [3+2] cycloaddition reaction between 2,3,4,6-tetra-o-acetyl-β-D-glucopyranosyl azide and propynyl-3-[3-aryl-1,2,4-oxadiazol-5-yl] propionates using copper as catalyst. The ester was prepared by reaction of benzamidoximes with succinic anhydride at 120^o-130^o, under solvent free conditions resulting in 3-aryl-1,2,4-oxadiazoles, which is then esterified using propargyl alcohol. The cycloaddition was carried out using Copper acetate and sodium ascorbate as catalyst dissolved in 1:1 dichloromethane: water to give the final product²⁰.

Boger et al. reported the synthesis of α-keto-1,2,4-oxadiazole derivatives using one pot synthesis method. For preparation of 1,2,4-oxadiazole, TBS protected cyanohydrin was treated with hydroxylamine and was converted to N-hydroxy-carbamide, which was then converted to diacyl hydrazide on reaction with acid chlorides. The reaction was carried in triethyl amine. The diacyl hydrazide was dehydrated on treatment with p-toluene sulphonyl chloride at high temperature and 1,2,4-oxadiazole was obtained²¹.

Huhtiniemi et al. synthesized oxadiazole-carbonylaminothioureas and oxadiazole-carbonylaminoureas using hydroxyamidines prepared from arylnitriles and hydroxylamine in the presence of aqueous ethanol. To hydroxyamidines was added ethylchloroacetate taken in dry pyridine or DCM to give ester derivative of 1,2,4-oxadiazole which was then converted to hydrazine derivative of oxadiazole by stirring with hydrazine monohydrate in ethanol. The hydrazine was converted to desired oxadiazole-carbonylaminothioureas and oxadiazole-carbonylaminoureas by stirring over night at room temperature with appropriate isocyanate or isothiocyanate in DMF²².

Ivachtchenko et. al. established the synthesis of N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides, by reacting nitriles with hydroxylamine in ethyl alcohol-water mixture in the presence of sodium bicarbonate to give amidoximes, which were then dissolved in chloroform and refluxed for 5hrs in pyridine with ethyl chloroxalate to give 3-heteroaryl substituted ethyl-1,2,4-oxadiazoles-5-carboxylates. The latter is then reacted with N-aryl substituted -3-piperazin-1-ylpropan-1-amines to give desired product (Scheme-5)²³.

Scheme-5

Ono et al. developed 3,5-diphenyl-1,2,4-oxadiazoles by the condensation of 4-bromobenzamidoxime with 4-nitrobenzoic acid and 4-methoxybenzoic acid. The reaction was carried out in the presence of DCC, HOBT and DMF²⁴.

Tiwari et al. synthesized 3-(5-bromo-2,3-dimethoxy-phenyl)-[1,2,4]oxadiazole derivatives using N-tert-butyl-5-bromo-2,3-dimethoxy-benzamide which was converted to 5-bromo-2,3-dimethoxybenzonitrile on reaction with phosphorus oxychloride, which was then converted to 2,3-dimethoxy-5-bromo benzamide oxime on reaction with hydroxyl amine in the presence of base. 2,3-dimethoxy-5-bromo benzamide oxime was converted to desired 3-(5-bromo-2,3-dimethoxy-phenyl)-[1, 2, 4] oxadiazole derivatives by reaction with alkyl methyl esters²⁵.

Cushman et al. synthesized a new class of alkenyldiaryl methanes (ADAMs) by replacing methyl ester group on phenyl ring with 3-methyl-1,2,4-oxadiazol-5-yl system. The drug was synthesized starting from tert-butyl hex-5-ynoate and methyl 5-iodo-2-methoxy-3-methylbenzoate undergoing Sonogashira coupling to give methyl 5-(6-tert-butoxy-6-oxohex-1-ynyl)-2-methoxy-3-methylbenzoate, which was then hydrostannated to yield an ester and then to a carboxylic acid on treatment with LiOH in dioxane-water. The carboxylic acid was then coupled with methoxyamine in the presence of EDCl to give N-methoxyamide. The compound thus formed was made to undergo stille coupling with 5-iodo-3,7-dimethylbenzo[d]oxazol-2(3H)-one. The coupled product was the fluorinated with DAST in the presence of methylene chloride and was converted to imidoyl fluoride and the tert-butyl group was removed using TMSOTf-Et₃N. The addition of 3-methyl-1,2,4-oxadiazole ring system was then carried out by reaction with acetamide oxime in the presence of O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU)²⁶.

Lankau et al. reported the synthesis of 3-aryl-1,2,4-oxadiazoles and 5-aryl-1,2,4-oxadiazoles (Scheme 3). 3-aryl-1,2,4-oxadiazoles were reported to be prepared by direct alkylation of imidazole or triazole with 3-aryl-5-chloromethyl-1,2,4-oxadiazole, using acetone and potassium carbonate. 5-chloromethyl-1,2,4-oxadiazoles intermediates were prepared by reaction of N-hydroxy benzamidines with chloroacetic acid in equimolar concentration. Further, 5-aryl-3-chloromethyl-1,2,4-oxadiazole intermediates were prepared by the reaction of 2-chloro-N-hydroxy acetamidines with substituted benzoyl chlorides²⁷.

Boys et al. reported the synthesis of β-substituted 1,2,4-oxadiazole butanoic acids by the reaction of hydroxyamidine with 3-substituted or 3,3-disubstituted glutaric anhydrides resulting in formation of 1,2,4-oxadiazole ring with substituted butanoic acid. The compound thus formed is a racemic mixture²⁸.

Palmer et al. synthesized keto-1,2,4-oxadiazoles containing tryptase inhibitors using commercially available N-α-benzyloxycarbonyl-N-ε-tert-butyl-oxycarbonyl-L-lysine, by converting to N-α-allyloxycarbonyl derivative via the Weinreb-amide, which was then reduced to Aldehyde and then converted to cyanohydrins formed as diastereomers, by reaction with acetone cyanohydrins. The substituted cyanohydrins were then protected as diastereomeric TBS ethers and in the presence of aqueous hydroxylamine in ethanol at 50°C was converted to N-hydroxy-amidines. N-hydroxy-amidines were then coupled with N-hydroxysuccinimidoyl ester, prepared by coupling 3,4-dichlorophenyl ethanol and methyl 4-hydroxyphenyl acetate, to give ester which was then heated in toluene for cyclization and thus giving 1,2,4-oxadiazoles, which are then N-α-deprotected via Pd-catalysed reductive cleavage using tributyl stannane. The derivatives of substituted 1,2,4-oxadiazoles were prepared via reaction with acylating agents (eg Acid chloride, aminocarbonyl chloride, isocyanate), followed by deprotection of the silyl group using TBAF to give alcohols. The alcohols were then oxidized to give Boc protected derivatives which then underwent HCL mediated deprotection of the N-ε group to give the desired product²⁹.

Cai et al. reported the synthesis of 3-Aryl-5-aryl-1,2,4-oxadiazoles via the reaction of substituted-N-hydroxybenzamidine or N-hydroxypyridinecarboxamidine with substituted arylcarbonyl chloride. Substituted-N-hydroxybenzamidine and N-hydroxypyridinecarboxamidine were prepared by the reaction of substituted benzonitrile or pyridinecarbonitrile with hydroxylamine, using ethanol and THF as reaction medium (Scheme-25a). Furan derivatives of 1,2,4-oxadiazole were synthesized from 3-bromofuran and 3-chlorofuran, by the reaction with lithium diisopropylamide to give 3-bromofuran-2-carboxylic acid and 3-chlorofuran2-carboxylic acid respectively. The carboxylic acid derivative is then converted to carbonyl chloride by the reaction with thionyl chloride and then to 5-(3- bromofuran-2-yl)-3-aryl-1,2,4-oxadiazoles and 5-(3- chlorofuran-2-yl)-3-aryl-1,2,4-oxadiazoles, respectively, by the treatment with N-hydroxyaryl-2-carboxamidine³⁰.

Wells et al. reported the synthesis of 3,5-diaryl-1,2,4-oxadiazoles and 3,5-diarylisoxazoles. 1,2,4-oxadiazoles were prepared by the reaction of amidoximes with 4-methoxy benzoyl chloride using pyridine as reaction mixture. The product thus formed was then deprotected with to give phenol and was then alkylated with substituted chloro alkyl amine to give ether. Isoxazoles were prepared by nitrile oxide [3+2] dipolar cycloaddition reaction between substituted chloro oxime and phenyl acetylene derivatives³¹.

Werbovetz et al. reported the synthesis of 5-thiocyanatomethyl- and 5-alkyl-3-aryl-1,2,4-oxadiazoles via the reaction of benzonitriles and hydroxylamine hydrochloride in ethanol to give benzamidoximes. The reaction was carried out in the presence of 8-hydroxyquinoline. Benzamidoxime was converted to O-acyl adducts by the reaction with chloroacetyl chloride, bromoacetyl bromide or bromoacetyl chloride, in the presence of potassium carbonate and acetone, which was then converted to halomethyl oxadiazoles by refluxing in toluene. Halomethyl oxadiazoles were then treated with ammonium thiocyanate in DMF to give desired methyl thiocyanates³².

Hernandez et al. established the synthesis of 3-substituted 1,2,4-oxadiazole from Fmoc-protected aspartyl derivatives. A solution of Fmoc-amino acid and Amidoxime was prepared in DCM/DMF, butanol and DIC, and stirred to give O-Amino acyl amidoximes which was then converted to substituted 1,2,4-oxadiazoles, by stirring with a solution of sodium acetate and heated at 86°C for 2-5hrs. the resulting mixture was then cooled to room temperature, and the solid oxadiazole was collected³³.

Wang et al. reported the synthesis of 4,5-dihydro-1,2,4-oxadiazoles on PEG support. The aldehyde was initially attached to PEG 4000 by esterification of p-formyl benzoic acid and PEG in the presence of DCC and DAMP in anhydrous dichloromethane at room temperature for 24hrs. The polymer-aldehyde complex was then converted to oxime by the reaction with hydroxylamine hydrochloride, in the presence of trioctylamine and dichloromethane at room temperature, which was later converted to the desired product, in the presence of NCS, trioctyamine, dichloromethane and excess of imine. Polymer support was removed by the reaction of oxadiazole with sodium methoxide in methanol³⁴.

Gangloff et al. reported the synthesis of 1,2,4-oxadiazoles from alkanoyl- and aroyl-oxyamidines using tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF). The amidoximes were prepared using hydroxylamine hydrochloride and aldehydes, which on treatment with TBAF, however, was converted to 1,2,4-oxadiazole. TBAF reduced the reaction time, when used as 1.0 equivalent. Further, THF was found to be better solvent than methylene chloride, but is equally comparable as acetonitrile³⁵.

MEDICINAL APPLICATIONS:

1,2,4-oxadiazoles shows a wide range of pharmacological actions such as in treatment of Alzheimer’s disease, antitumor agents, anti-inflammatory agents, anti-convulsant agent, Anti-HIV, determination of β-amyloid plaques in Alzhiemer’s disease.

1. Cytotoxicity:

Polothi et at. evaluated synthesized 1,2,4-Oxadiazoles for anticancer activity on MCF-7 (lung cancer), A549, MDA MB-231(breast cancer) cell lines by MTT assay and using doxorubicin as control. Out of 10 tested compounds four compounds showed IC₅₀ value in the range of 0.34+0.025 and 2.45+0.23μm⁷.

Srivastava et al. reported the cytotoxic activity of glycosyl-triazole linked 1,2,4-oxadiazoles in NCl-H₂₉₂ (lung carcinoma) and HEp-2 (larynx carcinoma) cell lines. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used for cytotoxic assay. Among tested compounds two of the glycosyl-triazole linked 1,2,4-oxadiazoles containing p-bromophenyl and p-nitrophenyl substitution showed 22-25% inhibition in cell growth²⁰.

Figure-1: Structure of compounds: i): 3-(3-Phenyl-1,2,4-oxadiazol-5-yl) propionic acid prop-2-ynyl ester ii): glycosyl-triazole linked 1,2,4-oxadiazoles

Cai et al. described 3-aryl-5-aryl-1,2,4-oxadiazoles as potent apoptosis inducers and anticancer agents tested via caspase and cell based high throughput screening assay against breast (T47D) and colorectal (DLD-1) and non-small cell lung cancer (H1299) cell lines. The ability to induce apoptosis calculated as ED₅₀, was maximum for 5-(3-chlorothiophen-2-yl)-3-(4-trifluoromethyl phenyl)-1,2,4-oxadiazole³⁰.

Figure-2: 3-aryl-5-aryl-1,2,4-oxadiazole

2. Alzheimer’s disease:

Ono et al. evaluated 3,5-Diphenyl-1,2,4-oxadiazole derivatives as probes for in-vivo imaging of β-amyloid plaques. The compounds were evaluated depending on affinity to inhibit binding of [¹²⁵I] IMPY with Aβ (1-42) aggregate in terms of Inhibition coefficient (K_i) and was further evaluated by testing the degree of penetration in brain²⁴.

Figure-3: 3-(4-iodophenyl)-5-(4-substituted phenyl)-1,2,4-oxadiazole

3. Anti-convulsant agent:

Ubaradka et al. reported the anticonvulsant activity of 1,2,4-oxadiazole derivatives with 3,4-dihydro-2H-chromen-2-amine moiety using PTZ seizure model. Out of the fourteen tested compounds, eight were found to be better in anticonvulsant activity, as compared against diazepam while two compounds showed moderate activity¹⁶.

Lankau et al. reported the anti-convulsant activity of various 3- and 5-aryl-1,2,4-oxadiazoles in pentylenetetrazole (PTZ) and maximal electroshock seizure (MES) models. The compounds were found to act via positive modulation of GABA, but does not bind with benzodiazepine binding site and by blocking sodium channel. Compounds 5-((1H-imidazol-1-yl)methyl)-3-phenyl-1,2,4-oxadiazole, 5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole and 5-((1H-1,2,4-triazol-1-yl)methyl)-3-m-tolyl-1,2,4-oxadiazole were found to be potent sodium channel blockers, 5-((1H-1,2,4-triazol-1-yl)methyl)-3-phenyl-1,2,4-oxadiazole possed only GABA modulating activity, while 5-((1H-imidazol-1-yl)methyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole was found to be GABA modulator as well as sodium channel blocker. Highest therapeutic index was recorded for 5-((1H-imidazol-1-yl)methyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole and 5-((1H-1,2,4-triazol-1-yl)methyl)-3-phenyl-1,2,4-oxadiazole²⁷.

Figure-4: Structure: 5-((1H-imidazol-1-yl)methyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole

Figure-5: Structure: 5-((1H-1,2,4-triazol-1-yl)methyl)-3-phenyl-1,2,4-oxadiazole

4. Anti-inflammatory agents:

Ubaradka et al. screened 1,2,4-oxadiazole derivatives with 3,4-dihydro-2H-chromen-2-amine moiety for antiinflammatory activity using carrageenam-induced paw edema method against diclofenac sodium as standard drug. Four of the compounds showed 37, 40.9, 42.5 and 37.0% inhibition, while other tested compounds showed very low % inhibition and hence poor antiinflammatory activity¹⁶.

5. Anti HIV activity:

Cushman et al. reported the anti-HIV activity of 3-methyl-1,2,4-oxadiazol-5-yl bioisosteres similar in structure to Alkenyldiarylmethanes (ADAMs) used in the treatment of HIV-1 reverse transcriptase. Compound possess sub-micromolar range of anti-HIV-1_RF activity, with better half life and metabolic stability (t_1/261 hrs) then previously reported compounds. IC₅₀was found to be 0.67μM and EC₅₀ was 0.7μM and 0.24μM as determined against HIV-1_RF and HIV-1_III²⁶.

6. Anthelmintic activity:

Ainsworth et al. tested anthelmintics activity of substituted 1,2,4-oxadiazoles in Nematospirides dubius infected mice by giving drug via oral and subcutaneous route. Through both the routes 3-alkyl and 3-aryl-1,2,4-oxadiazoles were found to be effective while 5-substituted-1,2,4-oxadiazoles were inactive with both the routes³⁶.

7. Anti-Microbial Activity:

Karad et al. screened the synthesized 2-morpholinoquinoline derivatives of 1,2,4-oxadiazoles for anti-bacterial and anti-fungal activity using broth micro dilution method and minimum inhibitory concentration (MIC) was noted. Anti-bacterial activity was carried out against three Gram positive (Bacillus subtilis [B.S.], Clostridium tetani [C.T.] and Streptococcus pneumonia [S.P.]) and three Gram negative (Salmonella typhi [S.T.], Escherichia coli [E.C.] and Vibrio cholera [V.C.]) bacteria with microbial type culture collection (MTCC) using ampicillin, norfloxacin, chloramphenicol and ciprofloxacin as standard drugs. While the anti fungal activity as tested against Candida albicans [C.A.], Aspergillus fumigatus [A.F.] using nystatin and griseofluvin as standard anti-fungal drugs⁸.

Other Medicinal Applications:

Inspite of their application as anti-cancer, anticonvulsant, antiinflammatory, anti-HIV, anthelmintic, anti-microbial activity and in determination of β-amyloid plaques in alzhiemer’s disease, 1,2,4-oxadiazoles also finds application as anti-Parkinson’s agents²⁵, dipeptidomimetic³⁷, antihistaminic³⁸, tryptase inhibitor²⁹, and hence in asthma, muscarinic receptor agonist and antagonist^39,40, dopamine receptor (D₃) ligand⁹, sphingosine-1-phosphate receptor agonist⁴¹, GSK-3-kinase inhibitor²³, antimycobacterial agents¹⁸, DGAT-1 inhibitors¹⁷, inhibitors of fatty acid amide hydrolases, enzyme responsible for hydrolysis of lipid amides²¹, inhibitors of type 1 and type 2 of sirtuin type protein present in humans²², antagonists of Integrin α_vβ₃²⁸, antagonists of IL-8 receptors³¹ and also acts against kinetoplastids³².

CONCLUSION:

1,2,4-Oxadiazole can be synthesized in various way depending on derivative to be prepared, and starting material being substituted Amidoxime. The five membered heterocyclic ring shows a wide range of biological activities as determined by aminal activities and tested on human cell lines and micro-organisms.

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Received on 08.10.2019 Modified on 17.12.2019

Research J. Pharm. and Tech. 2020; 13(10):5026-5033.

DOI: 10.5958/0974-360X.2020.00880.X