Document Type : Review Article

Authors

1 Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar-522510, Guntur, India

2 Department of Chemistry, Loyola College, PB 3301, Sterling Road, Nungambakkam, Chennai- 600 034

3 Department of Chemistry (P.G.), S.V.R.M. College, Nagaram-522268, Guntur, India

4 Scrips Pharma, Mallapur-500 076, Hyderabad, India

Abstract

Molecules with 1,3,4-oxadiazole ring structures have potential pharmacological relevance. These organic molecules are potentially reported for their medicinal importance. In this mini-review, different strategies for the synthesis of biologically important molecules of 1,3,4-oxadiazole ring are briefly summarized. Antimicrobial, anticancer, anti-inflammatory, anti-tubercular, molluscicidal, hypoglycemic, anticonvulsant, and antiprotozoal activities of the title compounds are also briefly reviewed. Significant papers were chosen and compiled the report until March 2022.

Graphical Abstract

Strategies to Synthesis of 1,3,4-Oxadiazole Derivatives and Their Biological Activities: A Mini Review

Keywords

Main Subjects

  1. Introduction

Pharmacologically relevant heterocyclic compounds play a key role in the fight against diseases affecting both human and animal living organisms, as well as plants. Finding out about new molecules with a potential biological effect, not yet described in the literature, is one of the most important aspects in the development of medicine, agriculture, and other allied sectors. Compounds showing desirable biological activity include heterocyclic moieties such as 1,3,4-oxadiazoles. Oxadiazole is a heterocyclic compound which has the molecular formula C2H2N2O. 1,3,4-Oxadiazole (Figure 1) is one of the four isomers of oxadiazole [1-2].

Figure 1. Structures of oxadiazole isomers

There are several studies which indicate that compounds with the 1,3,4-oxadiazole ring in their structure have a multidirectional pharmacological action [3-13]. Derivatives of 1,3,4-oxadiazole have antibacterial [14], antimalarial [15], anti-inflammatory [16], anti-depressive [17], anticancer [18], analgesic, and antiviral [19] effects. The anti-cancer effects of 1,3,4-oxadiazole derivatives appear to be of special interest, given the ever-increasing incidence of many types of cancer. 1,3,4-Oxadiazole, itself is not commonly used in organic chemistry, but many of its derivatives have biological activities [20-21] and are used in the medicinal field [22-25]. The stable oxadiazoles appear in a many pharmaceutical drugs which include raltegravir, fasiplon, butalamine, oxolamine, pleconaril, and nesapidil. Few examples of drugs which possess 1,3,4-oxadiazole rings are displayed in Figure 2.

Figure 2. Pharmacologically relevant drugs containing 1,3,4-oxadiazole rings

In continuation of our vast experience in the chemistry of oxadiazoles, we, herewith, present a brief compilation of both synthetic strategies and biological activity of the title compounds [26-30].

  1. Synthetic strategies for 1,3,4-oxadiazole

As depicted in Figure 3, 1,3-dibromo-5,5-dimethyl hydantoin is an efficient oxidizing agent for cyclization reactions involving acyl thiosemicarbazides (2) to produce 5-aryl-2-amino-1,3,4-oxadiazoles (3). The fundamental advantage of this protocol [31] is that the reagents utilized are inexpensive and safe to use in large-scale synthesis where alternative oxidizing agents are unavailable.

Figure 3. Synthesis of 5-aryl-2- amino-1,3,4-oxadiazoles

The synthesis of 5-substituted-1,3,4-oxadiazole-2-thiol (thione) 4 was reported by Koparir et al. [32], which requires an initial reaction between an acyl hydrazide and CS2 in a basic alcoholic solution, followed by acidification of reaction mass as illustrated in Figure 4. According to a literature review, this method is used to make a wide range of 1,3,4-oxadiazole derivatives. For such compounds, thiol 4-thione 5 tautomerism is known, and one of the two forms frequently predominates.

Figure 4. Synthesis of 5-substituted-1,3,4- oxadiazole-2-thiol (thione)

The preparation of 5-((naphthalen-2-yloxy) methyl)-N-phenyl-1,3,4-oxadiazol-2-amine (7) in reasonable yield by heating 2-[(naphthalen-2-yloxy)acetyl]-N-phenylhydrazine carboxamide (6) ethanol in the presence of NaOH and I2 in KI is another interesting approach reported by El-Sayed et al. [33] (Figure 5).

Figure 5. Synthesis of 5-((naphthalen-2-yloxy) methyl)-N-phenyl-1,3,4-oxadiazol-2-amine

Jha et. al. [34] explored the synthesis of 1,3,4-oxadiazole with 2,5-disubstitution (8) by cyclization process with substituted aromatic hydrazides in CS2 and aromatic acids in POCl3 almost a decade ago (Figure 6).

Figure 6. Synthesis of 1,3,4- oxadiazole

An imine CH functionalization of N-arylidene aroyl hydrazide with a catalytic amount of Cu(OTf)2 has provided ready access to symmetrical and unsymmetrical 2,5-disubstituted-[1,3,4]-oxadiazole 9. This is the most common example of amidic oxygen acting as a nucleophile in an imine CH bond oxidative coupling catalyzed by Cu catalyst [35]. These reactions may be carried out in a natural environment with air and moisture, making them extremely helpful in the preparation of organic molecules (Figure 7).

Figure 7. Synthesis of symmetrical and unsymmetrical 2,5- disubstituted-[1,3,4]-oxadiazole

Gaonkar et al. [36] described the oxidative cyclization of N-acyl hydrazones by chloramine-T under microwave irradiation to produce corresponding 5-substituted 1,3,4-oxadiazoles 10 (Figure 8).

Figure 8. Synthesis of 5-substituted 1,3,4-oxadiazoles

A range of symmetrical and asymmetrical 1,3,4-oxadiazoles with aryl, alkyl, and vinyl substitutions at 2,5-positions were synthesized in a skilled and diversified method [37]. With potassium carbonate, 1,3,4-oxadiazoles 11 were synthesized utilizing substituted aryl hydrazones and stoichiometric molecular iodine, which is a viable and transition metal-free oxidative cyclization of crude acyl hydrazones generated via condensation of aldehyde and hydrazide (Figure 9).

Figure 9. Synthesis of symmetrical and asymmetrical 2,5-disubstituted 1,3,4-oxadiazoles

Iodine-mediated oxidative C-O formation via condensation of a variety of aldehydes and semicarbazide was used to make 2-amino-substituted 1,3,4-oxadiazoles 12 [38] (Figure 10). This approach is a non-metal sequential procedure with aliphatic, aromatic, and cinnamic aldehydes which yields 2-amino substituted-1,3,4-oxadiazoles in a fast and versatile manner.

Figure 10. Synthesis of 2-amino-substituted 1,3,4-oxadiazoles

Using CBr4 as a bromine source, an extremely effective eosin Y catalyzed oxidative hetero-cyclization of semi-carbazone was developed using visible light photo redox catalysis [39]. This methodology provided a fastest, smooth, and operational admission to substantial 5-substituted 2-amino-1,3,4-oxadiazoles 13 (Figure 11).

Figure 11. Synthesis of 5- substituted 2-amino-1,3,4-oxadiazoles

Through consecutive isocyanide additions into NH and OH bonds of hydrazides [40], a novel Pd-catalyzed oxidative annulations reaction was produced, allowing impactful access to beneficial 2-substituted amino-1,3,4-oxadiazole 14, as illustrated in Figure 12.

Figure 12. Synthesis of 2-substituted amino-1,3,4-oxadiazole

A simple one-pot protocol [41] for preparation of a range of 2,5-disubstituted-1,3,4-oxadiazoles 15 was described by condensing monoaryl hydrazides with acid chlorides in solvent HMPA under microwave heating, as shown in Figure 13. The yields were found good to excellent, the technique was fast, and there was no need for an acid catalyst or a dehydrating agent.

Figure 13. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles

The ready formation of 5-substituted 2-(N-alkyl/aryl)-1,3,4-oxadiazoles 16 was accounted for using a simple and broad convention [42]. In this case, hydrazide was acylated with the appropriate isothiocyanate to produce thiosemicarbazide, which was subsequently treated with tosyl chloride/pyridine for intervening cyclization to obtain 5-substituted 2-(N-aryl/alkyl)-1,3,4-oxadiazoles 16 (Figure 14).

Figure 14. Synthesis of 5-substituted 2-(N-alkyl/aryl)-1,3,4-oxadiazoles

Ramazani et al. [43] reported a one-pot synthesis of the 2,5-disubstituted 1,3,4-oxadiazole derivative 17 in CH2Cl2 at room temperature with high yields utilizing (N-isocyanimino) triphnylphosphorane, a 20 amine, a carboxylic acid, and an ArCHO (Figure 15).

Figure 15. Synthesis of 2,5-disubstituted 1,3,4- oxadiazole derivative

Brain et al. [44] developed a novel methodology for generating 1,3,4-oxadiazoles 18 from 1,2-diacylhydrazines reacting with Burgess reagent under microwave conditions (Figure 16).

Figure 16. Synthesis of 1,3,4-oxadiazoles

  1. Pharmacological activities and recent advances

A wide range of biological actions have been discovered in 1,3,4-oxadiazole derivatives such as antibacterial, anticancer, anti-inflammatory, anticonvulsant, pesticide, monoamine oxidase inhibitors (MOA), antihypertensive, and other properties, etc.

3.1. Antimicrobial activities

5-(5-methylisoxazole-3-yl)- 3-substituted aminomethyl-2-thio-1,3,4-oxadiazoles 19, 4-acetyl-2-thio-1,3,4-oxadiazoles (5-methylisoxazole-3-yl) 2-aryl-5-9 and -5-substituted 1,3,4-oxadiazoles 20 (5-methylisoxazole-3-yl)-1,3,4-oxadiazoles 21 were synthesized using the Mannich reaction [45], and their anti-bacterial activation against Staphylococcus aureus, Escherichia coli, and Bacillus subtilis was evaluated by cup plate procedure at 100 g/mL. 4-Acetyl-2-phenyl-(5-methylisoxazole-3-yl) 2-aryl-5-9-substituted 1,3,4-oxadiazoles and 5-substituted 1,3,4-oxadiazoles (5-methylisoxazole-3-yl) were found to be the most active candidates in this family of 1,3,4-oxadiazoles (Figure 17).

Figure 17. Family of 1,3,4-oxadiazoles exhibiting antimicrobial activity

Some new 1,2,4 triazolo-1,3,4-oxadiazole derivatives 22, oxa-di-azolo [1,3,5]-triazine 23, and triazolo-1,3,4-oxadiazole 24 were tested (Figure 18) for their anti-bacterial activity in vitro on Gram-negative bacteria (S. typhi and E. coli.) and Gram-positive bacteria (S. aureus) by Mulwad and Chaskar [46]. Tube dilution techniques were used to determine the minimum inhibitory concentration (MIC) of ciprofloxacin, cloxacillin, and gentamicin. The majority of the compounds in this class have been found to have considerable biological action.

Figure 18.

The preparation of 5-(2,4-dichloro-5-fluorophenyl) -3-[(substituted-amino)methyl]-1,3,4-oxadiazole-2(3H)-thione 27 and 2-oxadiazole-2(3H)-thione (2,4-dichloro-5-fluorophenyl) -5-(substituted-sulfanyl) -1,3,4-oxadiazole 28 has been reported [47] and evaluated for antibacterial property on S. aureus, E. coli, and K. pneumonia by a serial dilution technique using nitrofurazone as the reference drug. The majority of tested chemicals were active in a similar range to the standard [48]. It’s possible that the presence of 2,4-dichloro-5-fluorophenyl and 4-chloroaryloxy methyl groups explains the reason for the activity (Figure 19).

Figure 19.

3.2. Anti-cancer activities

2-Chloro-3-{5-[(2-substituted-1-H-benzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}quinoline 29 and 2-chloro-3-(5-substituted-phenyl-1,3,4-oxadiazol-2-yl)quinoline 30 (Figure 20) were prepared [49] and screened for anti-cancer property against to 60 cancer cell line at a dose of 10−5 Molar on different broad cell lines.

Figure 20. Family of 1,3,4-oxadiazoles exhibiting anti-cancer activity

Steroidal derivatives of 3b-[5′-mercapto-1,3,4-oxadiazole-2-yl] methoxycholest-5-ene 31 (Figure 21) were prepared and tested for anti-cancer property over human leukemia (HL-60) cell line using MTT assay [50] and found IC50at 17.

Figure 21.

The 2-chloro-1,4-bis-(5-substituted-1,3,4-oxadiazol-2pheylmethyleneoxy)phenylene derivative 32 was synthesized (Figure 22) and tested in vitro on NCI-60 cancer cell lines of various cancer types, as well as leukaemia, CNS, colon, melanoma, lung, renal prostate, ovarian, and breast cancer. Most cancer cell lines demonstrated substantial action against the molecules with R= 2,4-dicholoro C6H3OCH2 and 4-ClC6H4NHCH2 [51].

Figure 22.

As monastrol analogues, a novel series of dihydropyrimidine derivatives containing the 1,3,4-oxadiazole moiety was created. 4-(3-Chlorophenyl)-2-(((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)thio)-6-methyl-1,4-dihydropyrimidine-5-carboxylateb 33 and ethyl 2-(((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)thio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 34 were discovered active among all [52]. MOLT-4 (IC50 80 nM) and leukaemia HL-60TB (IC50 56 nM) were the most sensitive cell lines and were found to be more potential than monastrol (IC50=215 and 147 nM, respectively) (Figure 23).

Figure 23.

Kapoor et.al. [53] synthesized a series of 2-(substituted phenyl)-5-(2-(2-(substituted phenyl)-1H-benzo[d]imidazol-1-yl) phenyl)-1,3,4-oxadiazoles 35 (Figure 24) and tested for anti-tumor activity against breast cancer cell lines (MCF-7) by MTT assay. The substitutions with R1=4-OCH3, and R2=4-OCH3 compound exhibited excellent cytotoxic activity.

Figure 24.

3.3. Anti-inflammatory activities

1-{5-(4-Hydroxy-phenyl)-3-[5-(1H-indol-3-ylmethyl)-4H-pyrazol-3-ylamino]-4,5-dihydro-pyrazol-1-yl}-ethanone (R=p-OHC6H5) 36 was synthesized [54] and tested, and also their anti-inflammatory activity with inhibition at a dose at 50 mg kg-1 (Figure 25).

Figure 25. Family of 1,3,4-oxadiazoles exhibiting anti-inflammatory activity

5-Pyridyl-1,3,4-oxadiazole-2-thiol 37 and S-benzoyl-5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol [55] 38 analogs were synthesized and evaluated for anti-inflammatory activity against indomethacin as standard with 40.7 and 39.2% inhibitions, respectively (Figure 26).

Figure 26.

A series of 2,5-disubstituted-1,3,4-oxadiazole compounds, 5-(2,4,6-trichlorophenoxy methyl)-2-mercapto-1,3,4-oxadiazole 39, 2,4-dichlorophenyl- 5-(2,4,6-trichlorophenoxy methyl)-1,3,4-oxadiazole 40, and 1-(4-isobutylphenyl) ethyl-5-(2,4,6-trichlorophenoxy methyl)-1,3,4-oxadiazole 41 were synthesized [56] and tested in vivo for their anti-inflammatory activity (Figure 27).

Figure 27.

3.4. Anti-tubercular activities

Aryl sulfonamido-5-[2′-(benzimidazol-2″-yl)]-1,3,4-oxadiazoles 42 and 2-benzoylamino-5-[2′-(benzimidazol-2″-yl)phenyl]-1,3,4-oxadiazoles 43 were prepared (Figure 28) and studied for anti-tubercular property against H37Rv in BACTEC 12B medium using BACTEC 460 radiometric system [57].

Figure 28. Family of 1,3,4-oxadiazoles exhibiting anti-tubercular activity

A new sequence of substituted sulfanyl-1-[5-substituted-1,3,4-oxadiazol-2-yl]-derivatives of 1H-benzimidazole 46 were created with the goal of discovering a more effective anti-inflammatory and antitubercular property. Middle brook 7H9 agar media was used to screen all of the compounds for anti-tubercular activity against the H37Rv strain. The anti-tubercular action of compounds containing R=phenyl, 2-hydroxyphenyl, and 4-aminophenyl has been found good [58] (Figure 29).

The novel series of 2,5-disubstituted-1,3,4-oxadiazoles 45 were produced and tested for anti-tubercular activity against the H37Rv strain using middle brook 7H9 agar media. Compounds with R with 4-aminophenyl and Ar with phenyl substituent indicated promising anti-tubercular activity (Figure 29).

Figure 29.

3.5 Molluscicidal activities

Nizamuddin and Singh presented the preparation of 2-phenyl-spiro(cyclohexane)-1′,5-[1,3,4] oxadiazolo[3,2-c]thiazoline analogue 47 (Figure 30) tested for molluscicidal activity against Lymnaea acuminata and found greater activity among others [59].

Figure 30. Family of 1,3,4-oxadiazoles exhibiting anti-molluscicidal activity

3.6 Hypoglycemic activities

Hussain and Jamali synthesized [60] 2-arylamino-5-[p-(3-aryl-4-oxoquinazoline-2-yl methyl amino)phenyl]1,3,4-oxadiazoles 48 and evaluated for hypoglycemic property (Figure 31).

Figure 31. Family of 1,3,4-oxadiazoles exhibiting anti-hypoglycemic activity

5-alkyl-2-aryl sulfonamido-l,3,4-oxadiazoles 49 derivatives were synthesized and tested for hypoglycemic activity. Among that, R= p-amino group were found as a prerequisite for excellent hypoglycemic property (Figure 32).

Figure 32.

3.7 Anticonvulsant activities

Almasirad et al. [61] presented the preparation of a sequence of novel 2-substituted-5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles 50 and the evaluation of their anticonvulsant properties. In both the PTZ and the maximal electroshock seizure (MES) models, the compound containing an -NH2 substituent at the 2nd position on oxadiazole ring exhibits the highest anticonvulsant effect (Figure 33). In a PTZ test, the effect was blocked by flumazenil, a benzodiazepine antagonist, indicating that benzodiazepine receptors are involved in this impact [62].

Figure 33. Family of 1,3,4-oxadiazoles exhibiting anti-convulsant activity

2-Arylsulphonamido-5-(α-methyl-4-isobutylbenzyl)-1,3,4-oxadiazoles 51 and substituted benzamido-5-(α-methyl-4-isobutylbenzyl)-1,3,4-oxadiazoles 52 were synthesized and screened for anticonvulsant property by MES and subcutaneous pentylenetetrazole (scPTZ) approaches [63].

Figure 34.

The anticonvulsant property of a sequence of 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles 53 was investigated. In both the PTZ and MES designs, the molecule with an amino substituent at the 2nd position of the oxadiazole ring and a fluoro substituent at the p- position of the benzyloxy group exhibited encouraging results (Figure 35). The activity was stopped when the fluoro substituent was replaced with a bigger electron-withdrawing group, such as chlorine.

Figure 35.

Anticonvulsant drugs have been devised and synthesized using a sequence of novel 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles 54. The insertion of an amino group at the 2nd position of 1,3,4-oxadiazole ring and a fluoro substituent at the p-position of the benzylthio group provided the best anticonvulsant action in electroshock and pentylenetetrazole-induced convulsion tests [64] (Figure 36).

Figure 36.

3.8 Anti-protozoal activities

New 5-(3,5-disubstituted-1H-indol-2-yl)-1,3,4-oxadiazole-2(3H)-thione and 2-[5-(3,5-disubstituted-1H-indol-2-yl)-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]acetohydrazides were synthesized and evaluated for potential anti-helmintic property on Pheratimaposthuma using piperazine citrate 2 mg ml-1 as standard. 3-Ethyl-5-(5-methyl-3-phenyl-1H-indol-2-yl)-1,3,4-oxadiazole-2(3H)-thione 55 and 3-benzyl-5-(5-methyl-3-phenyl-1H-indol-2-yl)-1,3,4-oxadiazole-2(3H)-thione 56 were two tested molecules with better activity among the most common compounds in this series [65] (Figure 37).

Figure 37. Family of 1,3,4-oxadiazoles exhibiting anti-protozoal activity

  1. Conclusions

In this review, the authors successfully described the significant syntheses of 1,3,4-oxadiazole derivatives that have been published during the last decade. Oxadiazole derivatives reveal a wide range of biological activity and drug discovery programs. We believe oxadiazole research is still in the early stage, and huge potential remains unexploited in many fields, further study will open a new era of scientific development particularly novel reactions and applications in organic synthesis methodologies by creative chemists will certainly allow the access to challenging targets in an extremely efficient manner.

 

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