1,2,4-Oxadiazoles: A potential pharmacological agents-An overview
Ajay Kumar K.1*, Lokeshwari D.M.1, Pavithra G.2 and Vasanth Kumar G.1
1Post Graduate Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore, India.
2Department of Chemistry, JSS College for Women, Saraswathipuram, Mysore, India.
*Corresponding Author E-mail: ajaykkchem@gmail.com
ABSTRACT:
Drug discovery and development is a multidisciplinary, creative, innovative and highly regulated process. Finding a successful lead has been a great challenge in pharmaceutical research and is utmost important in the formulation development. Optimization of the process used to manipulate the compound to improve its chemical stability, potency, biological or therapeutic effectiveness. Literature survey reveals 1,2,4-oxadiazoles are statistically significant in bioorganic and pharmaceutical chemistry. They were known to exhibit varied pharmacological properties. This review article provides up to date information about developments, exploration of new methods, techniques adopted for the synthesis of 1,2,4-oxadiazoles, their transformation to biologically important derivatives, and studies on their pharmacological properties.
KEYWORDS: Amidoximes, oxadiazoles, antitumour, antioxidant, antiinflammatory.
INTRODUCTION:
Oxadiazoles and their derivatives can be considered as simple five membered heterocycles possessing one oxygen and two nitrogen atoms. The oxadiazoles exist in different isomeric forms such as 1,2,4-, 1,2,5-, 1,2,3- and 1,3,4-oxadiazoles (1a-d)1.
The five-member heterocyclic compounds; particularly 1,2,4-Oxadiazole have been successfully tested against several diseases and therefore received special attention in bioorganic and pharmaceutical chemistry due to their diverse medicinal applications. Numerous 1,2,4-oxadiazoles have been suggested as potential agonists for cortical muscarinic, benzodiazepine, and 5-HT1D (5-hydroxytryptamine) receptors, and as antagonists for histamine H3 receptors. They show activity as antirhinoviral agents, growth hormone secretagogues, anti-inflammatory agents, and antitumor agents.
They also inhibit the SH2 domain of tyrosine kinase, monoamine oxidase, human nuetrophil elastase, anti-Alzeimer’s, antiparasitic, anthelmintic, diuretic, antimicrobial, hypoglycemic, skeletal muscle relaxant, hypertensive activity, Anti-HIV and human DNA topoisomerases properties. Tropane derivatives of 1,2,4-oxadiazoles display high affininity for the cocaine binding site of the dopamine transporter. Oxadiazoles are heterocyclic compounds with a variety application in many pharmaceuticals and agrochemicals products.
The review describes the detailed information about synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds. The material in this survey includes some general features, state-of-the-art applications together with a critical discussion about current limitations and suggestions for future developments.
Synthesis of 1,2,4-oxadiazoles:
The usual synthesis of 1,2,4-oxadiazole involves the cyclocondensation reaction between amidoxime and carboxylic acids or acid anhydrides or acid halides or carboxylic acid esters. The most common routes to 1,2,4-oxadiazoles; couple amidoximes with: (i) activated carboxylic acid derivatives such as acid chlorides, fluorides, anhydrides, or active esters; (ii) carboxylic acids in the presence of coupling reagents including dicyclohexylcarbodiimide (DCC), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide (EDC), 1-(dimethylamino) isopropyl chloride (DIC)/HOBt, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), or 1,1’-carbonyldiimidazole (CDI). Other methods to obtain 1,2,4-oxadiazoles include reactions of amidoximes with aryl halides in the presence of palladium catalysts, or with aldehydes followed by oxidation.
For instance, 1,2,4-oxadiazoles are conveniently prepared in one step by the condensation of carboxylic acid esters and amidoximes in the presence of potassium carbonate. This method was found very useful in synthesizing a variety of mono- and bis- 1,2,4-oxadiazoles in excellent yields (Scheme-1)2.
The 5-substituted-3-trichloromethyl-1,2,4-oxadiazoles are more conveniently synthesized in one step by the reaction of trichoroacetoamidoxime with acyl chlorides (R= methyl ethyl, propyl, Ph, CH2Cl, CHCl2, CCl3) in toluene for 20 hours at 100°C (Scheme-2)3. The paper describes the substitution effect on the reaction rate, purity of the products and the yield.
A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described. An appropriate arylamidoxime was allowed to react with succinic anhydride in a domestic microwave oven following the procedure reported earlier to afford the products (Scheme-3)4.
A series of 3,5-disubstituted 1,2,4-oxadiazoles and their bioisosters synthesized were evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles involve coupling of amidoxime with an appropriate carboxylic acid followed by thermal cyclization. The results of the study revealed these compounds have significant activity against DU145 (IC50: 9.3 μM) cell lines. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity5. An amidoximes (2) were reacted with N-t-butoxycarbonyl-O-benzyl-L-aspartic acid (3) in the presence of dicyclohexylcarbodiimide (DCC) in dichloromethane at room temperature to produce condensed products (4), which on heating at 100-110 °C for 5 h yielded 3,5-disubstituted 1,2,4-oxadiazoles (5) (Scheme-4)6.
Series of 3-arylsulfonylmethyl-1,2,4-oxadiazole-5-carboxylic acid derivatives have been synthesized from the reaction of 2-(4-chlorophenylsulfonyl)acetamide oxime with ethyl oxalyl chloride. The products showed antihypertensive activity in rats, structural modifications to improve activity were discussed9. Aromatic amidoximes reacts with substituted diethyl malonate in the presence of DCC in dioxane to produce 2,5-disubstituted 1,2,4-oxadiazoles in relatively good yield (Scheme-6)10.
3-Nitro-5-guanidino-1,2,4-oxadiazole (NOG) was synthesized from diaminoglycoluril with in situ generated dimethyldioxirane (DMDO). The impact sensitivity of NOG is more than 40 J with a decomposition temperature of 290 °C. Some other energetic derivatives have been prepared and characterized11. The synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as an activating agent of the carboxylic acid function for the O-acylation step (Scheme-7)12. The method was used for the synthesis of a library of 1,2,.4-oxadiazoles.
1,3-Dipolar cycloaddition reactions of chiral imines obtained from optically active amino acids with nitrile oxides afforded 1,2,4-oxadiazole derivatives in moderate to good yields with good stereoselectivity. Investigation on the effect of bases suggested that triethylamine was prone to afford better stereoselectivity, while NaHCO3 was prone to increase the reaction rates and yields (Scheme-9)15.
Ajay Kumar and co-workers16 reported the synthesis of series of trisubstituted 1,2,4-oxadiazoles via 1,3-dipolar cycloaddition reactions. They carried out a cycloaddition reaction of imines and nitrile oxides generated in situ by the catalytic dehydrogenation of aromatic aldoximes using chloramine-T reagent and obtained the cycloadducts in good yield. The cycloadducts have been tested for their antifungal and antibacterial activity, results of their study revealed that all the cycloadducts exhibited a promising activity (Scheme-10).
Tetrabutylammonium fluoride (TBAF) was found to be a mild and efficient catalyst for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles. Using 0.1–1.0 equivalents of TBAF in THF for 1–24 hr at room temperature, alkanoyl- and aroyloxyamidines were converted in high yield to the corresponding 3,5-disubstituted-1,2,4-oxadiazoles. The n-Bu4NF catalyzed ring closure of acyloxyamidines afforded 1,2,4-oxadiazoles in good to high yield (Scheme-11)17.
Reactions of 1.2.4-oxadiazoles:
1,2,4-oxadiazoles are considered as useful intermediates in the synthesis of pharmacologically active molecules. For instance, 3,5-Diphenyl-1,2,4-oxadiazole is known to be stable under conditions of acid hydrolysis. The reaction of 5-trinitromethyl-3-phenyl-1,2,4-oxadiazole (6) with dilute (1:1) hydrochloric acid resulted in formation of benzamide oxime (7) via decomposition of the oxadiazole ring. Attempted selective hydrolysis of trinitromethyl group in (6) under mild conditions (acetic acid) afforded 5-hydroxy-3-phenyl-1,2,4-oxadiazole (8) (Scheme-13)20.
3-Aryl-5-phenylselenomethyl 1,2,4-oxadiazole reacts with allyl bromide in the presence of LDA at -78ºC to form an intermediate, which on oxidation with hydrogen peroxide undergo deselenenylation to form 3-aryl-5-butadienyl 1,2,4-oxadiazole en excellent yield (Scheme-14)8.
The photochemistry of some 1,2,4-oxadiazoles containing a double bond at the side chain has been investigated. The irradiation yielded different 2-N-benzoylamino-2-oxazoline derivatives depending on the employed reaction solvent (DCM or THF). Photorearrangements occur through an intramolecular aziridination reaction yielding a bicyclic intermediate, which was subjected to in situ aziridine ring opening. Photoinduced addition of HCl, involving the chlorinated solvent as a reagent, gave the corresponding chlorinated 2-oxazoline, while in THF; reductive aziridine ring opening took place (Scheme-15)21.
Catalytic hydrogenation of 5-substituted 3-(2-aminobenzyl)-1,2,4-oxadiazoles produced 2-(acylamino) indoles, which on treatment with acid leads to the novel 6-phenyl-8H-pyrimido[1,6-a: 4,5-b']diindoles. The method was considered as a route for the new ring formation22. The photochemical reaction of the arylhydrazones of 3-benzoyl-5-substituted-1,2,4-oxadiazoles was studied extensively. The effect of several modifications of the substrates structure (E and/or Z) of arylhydrazones, the possible presence of substituents in the arylhydrazono moiety, and the nature of substituents at C-5 of the 1,2,4-oxadiazole ring on the course of the photochemical rearrangement has been reported (Scheme-16)23.
Pharmacological applications of 1,2,4-oxadiazoles:
The 3-phenyl-5,8-diethylaminoethyl-1,2,4-oxadiazole has been studies extensively for its pharmacological properties. It was tested for anti-tussive activity of this drug is more apparent in tests involving a diffuse stimulation of the bronchial tree than with electrical stimulation of the superior laryngeal nerve. The results suggest a predominantly peripheral mechanism of action. These compounds also possesses analgesicanti-inflammatory, local anaesthetic and antispasmodic properties with low acute and chronic toxicities, and the experimental results indicate the absence of side effects24. 3,5-diaryl-1,2,4-oxadiazoles synthesized by condensation reaction of amidoximes with aromatic acid chloride. The synthesized compounds were evaluated for their anticancer activity using mice specific Ehrlich Ascites Carcinoma cell (EAC cells) in Swiss albino mice model. Most of the compounds (dose 25 mg/ kg body weight) showed significant reduction of tumor cell count as well as tumor weight, where as life span of the treated mice also increased25.
A series of 3,5-disubstituted-1,2,4-oxadiazoles prepared were evaluated for phosphodiesterase inhibition (PDE4B2). Among the series; 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole was found most potent inhibitor (IC50 = 5.28 μm). Structure–activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat26.
Metabolites of a G protein-coupled receptor (GPCR) modulator, containing 1,2,4-oxadiazole and piperazine substructures, were identified in vitro in human, rat and dog hepatocyte incubates and in vivo in rat plasma, bile, urine and feces using 14C radiolabeled parent compound. The exposure coverage for the major circulating metabolites in human at steady state by preclinical species used in drug safety assessment was determined using pooled plasma samples collected from a human multiple ascending dose study and the 3-month rat toxicokinetic study. Metabolites M1 and M2 formed by opening the 1,2,4-oxadiazole ring were observed as major metabolites, both in vitro and in vivoacross species. The carboxylic acid metabolite M2 was presumably formed via reductive N-O bond cleavage of the oxadiazole ring and subsequent hydrolysis27. Sulfide and sulfonyl derivatives of 1,2,4-oxadiazoles synthesized were screened by MTT assay on the prostate cancer cells (DU-145). The results revealed that some of these compounds found to be potential anti-prostate cancer agents with IC50 values ranging from 0.5 to 5.1 μM. These compounds also exhibited good activity on the androgen independent cells PC-3, and moderate on androgen dependent LNCaP cells. Also they showed very low cytotoxicity on non-cancerous cells MCF-10A28.
The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. The biophysical, computational characterization, structure-activity relationship, and physicochemical properties of a series of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole inhibitors of TNKS1 Wnt signaling pathway was well described29. A series of benzyl or aryl substituted 1,2,4-oxadiazole derivatives of phenylalanine synthesized were evaluated for their affinity to rat brain NK1-receptors and as inhibitors of a specific substance P cleaving enzyme, substance P endopeptidase (SPE), isolated from human cerebrospinal fluid. The results indicate that several compounds are weak inhibitors of SPE. However, all compounds lacked appreciable NK1-receptor affinity30.
The Linezolid-like molecules with oxazolidinone as central heterocyclic moiety with a 1,2,4-oxadiazole ring bearing different side-chains and containing a varying number of fluorine atoms were synthesized and screened for biological activity against some Gram-positive and Gram-negative bacteria31. Series of 3,5-disubstituted-1,2,4-oxadiazoles synthesized were evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity32.
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. One of the analogue (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy33. 1,2,4-Oxadiazole-based muscarinic agonists synthesised readily penetrate into the CNS. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base34.
The muscarinic pharmacology of a novel ±3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine has been studied using pharmacological, radioligand binding and biochemical techniques, in vitro in isolated tissue experiments. The experimental results revealed that these were more potent agonist than carbachol in all preparations studied, being most potent at muscarinic receptors mediating negative chronotropy in guinea-pig right, spontaneously beating atria and least potent at receptors mediating contractions in canine saphenous vein and endothelial denuded rabbit aorta respectively. This degree of selectivity was also observed in competition radioligand binding studies35. 1,2,4-oxadiazole derivative were exhibited amoebicidal activity. The detailed structure-activity relationship was well established36.
A series of 3- and 5-aryl-1,2,4-oxadiazole derivatives prepared were tested for anticonvulsant activity in a variety of models. These 1,2,4-oxadiazoles exhibit considerable activity in both pentylenetetrazole (PTZ) and maximal electroshock seizure (MES) models. The studies revealed that some of the compounds were protective in the PTZ model in rats with an oral ED50 of 25.5 mg/kg and in the MES model in rats with an oral ED50 of 14.6 mg/kg. Neurotoxicity was observed with an ED50 of 335 mg/kg. Also several oxadiazoles acted as selective GABA potentiating compounds with no interaction to the benzodiazepine binding site37. Replacement of the isothiourea moiety of known histamine H3 antagonists by certain 5-membered heteroaromatic systems can give compounds with an improved activity profile. One of these, 3-[(4-chlorophenyl)methyl]-5-[2-(1H-imidazol-4-yl)ethyl] 1,2,4-oxadiazole (GR175737) is a potent, selective, orally active and centally penetrating H3 antagonist38. Replacement of the isothiourea moiety of known histamine H3 antagonists by certain 5-membered heteroaromatic systems can give compounds with an improved activity profile. For instance, 3-[(4-chlorophenyl)methyl]-5-[2-(1H-imidazol-4-yl)ethyl] 1,2,4-oxadiazole is a potent, selective, orally active and centrally penetrating H3 antagonist. 5-amino-substituted 1,2,4-oxadiazoles synthesized conveniently by the reactions of amidoximes with carbodiimides were further converted to acetamide derivatives have been studied for their antioxidant activity. Most of the compounds exhibited in general low interaction with the stable DPPH radical. They were also studied in vivo for their anti-inflammatory activity using the carrageenin paw edema model and showed significant anti-inflammatory activity (51%), they also inhibited significantly soybean lipoxygenase39.
Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; Structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis40.
Apart from pharmacological properties, 1,2,4-oxadiazoles also exhibit significant physical properties. For instance, 3,5-disubstituted 1,2,4-oxadiazoles shows liquid crystal properties which exhibit spontaneous polarization in the smectic phase, even if there is no chiral group in the molecules41,42. Series of synthesized 1,2,4-oxadiazoles derived bent-core liquid crystals incorporated with cyclohexane rings were investigated for their liquid crystal properties, all the compounds exhibited wide ranges of nematic phases composed of tilted smectic (SmC-type) cybotactic clusters with strongly tilted aromatic cores (40-57°)43.
CONCLUSIONS:
In summary, the review presents traditional/conventional, and advanced methodology for the synthesis of pharmacologically important 1,2,4-oxadiazoles. Detailed discussion about their structure-activity relationship associated with diverse pharmacological activity. The article may become very useful source for the researchers to device new novel molecules bearing 1,2,4-oxadiazole moiety and to study their pharmacological properties.
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Received on 17.11.2012 Modified on 25.11.2012
Accepted on 28.11.2012 © RJPT All right reserved
Research J. Pharm. and Tech. 5(12): Dec. 2012; Page 1490-1496