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Design, synthesis and biological evaluation of 1,3,4-oxadiazoles as promising anti-inflammatory agents

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Abstract

A series of 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for radical scavenging and anti-inflammatory properties. Molecular docking simulation studies onto the proteins cyclooxygenase-1 (PDB: 1CQE) and cyclooxygenase-2 (PDB: 3LN1) to visualize the probable binding affinity towards anti-inflammatory importance and in silico studies, towards their appreciable ADME & probable toxicity property were screened. The best-ranked molecules; N-((5-substituted-1,3, 4-oxadiazol-2-yl)methyl) benzo[d]thiazol-2-amine (5a– 5j) were synthesized from 2-(benzo[d]thiazol-2-ylamino)acetohydrazide (4) on reaction with aryl/heteroaryl/aliphatic carboxylic acid derivatives via acid catalyzed dehydrative cyclization. N-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl) benzo[d]thiazol-2-amine (5k) was synthesized by base catalyzed condensation of hydrazide derivative 4 and with carbon disulfide. The newly synthesized compounds were characterized and established on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass studies. The 1,3,4-oxadiazoles were evaluated for in vitro antioxidant property by 2,2′-diphenyl-1-picryl hydrazyl radical scavenging assay method and in vivo anti-inflammatory activity by carrageenan induced paw edema method. The radical scavenging activity indicated that the 1,3,4-oxadiazoles at 25 µM test concentration exhibited significant radical scavenging property ranging from 32.0 to 87.3 % in comparison to 76.0 % radical scavenging activity obtained for the reference drug, ascorbic acid. The results of the in vivo anti-inflammatory activity highlighted that the 1,3,4-oxadiazoles at 25 mg Kg−1 test dose exhibited significant edema inhibition with a mean value ranging from 23.6 to 82.3 % in comparison to 48.3 % edema inhibition obtained for the reference drug, indomethacin. The compound 5h with mean edema inhibition value of 82.3 % and potent among the series was further evaluated for in vitro COX inhibition and was found to more selective towards COX-2. The acute ulcerogenic evaluation of compound 5h indicated it to be safe at the dose of 50 mg Kg−1.

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Acknowledgment

The authors are thankful to Principal, JSS College of Pharmacy, Mysuru and JSS University for providing us all necessary facilities. We sincerely extend our gratitude to chairman and staff, NMR research center, Mysore University, Mysore for providing NMR and mass spectra. Authors also beholden to DBT for the financial assistance (Ref. No: BT/PR5594/MED/29/540/20l2).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570 015, India

    Vishwanathan Balasubramanya Iyer, Bannimath Gurupadayya, Venkata Sairam Koganti, Bharthkumar Inturi & Ravandur Shivanna Chandan

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  1. Vishwanathan Balasubramanya Iyer
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  2. Bannimath Gurupadayya
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Correspondence to Vishwanathan Balasubramanya Iyer.

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Iyer, V.B., Gurupadayya, B., Koganti, V.S. et al. Design, synthesis and biological evaluation of 1,3,4-oxadiazoles as promising anti-inflammatory agents. Med Chem Res 26, 190–204 (2017). https://doi.org/10.1007/s00044-016-1740-6

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