Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Synthesis of 2-{[5-(aralkyl/aryl)-1,3,4-oxadiazol-2-yl]sulfanyl}-N-(4-methyl-1,3-thiazol-2-yl)acetamides: Novel bi-heterocycles as potential therapeutic agents

Muhammad S Ramzan¹, Muhammad A Abbasi¹ , Aziz-ur-Rehman ¹, Sabahat Z Siddiqui¹, Syed AA Shah^2,3, Muhammad Ashraf⁴, Muhammad A Lodhi⁵, Farman A Khan⁵, Bushra Mirza⁶

¹Department of Chemistry, Government College University, Lahore-54000, Pakistan; ²Faculty of Pharmacy; ³Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia; ⁴Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur-63100; ⁵Department of Biochemistry, Abdul Wali Khan University, Mardan-23200; ⁶Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan.

For correspondence:- Muhammad Abbasi Email: abbasi@gcu.edu.pk

Accepted: 19 April 2018 Published: 28 May 2018

Citation: Ramzan MS, Abbasi MA, A, Siddiqui SZ, Shah SA, Ashraf M, et al. Synthesis of 2-{[5-(aralkyl/aryl)-1,3,4-oxadiazol-2-yl]sulfanyl}-N-(4-methyl-1,3-thiazol-2-yl)acetamides: Novel bi-heterocycles as potential therapeutic agents. Trop J Pharm Res 2018; 17(5):913-926 doi: 10.4314/tjpr.v17i5.23

© 2018 The authors.
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Abstract

Purpose: To evaluate the therapeutic potential of new bi-heterocycles containing a 1,3-thiazole and 1,3,4-oxadiazole in the skeleton against Alzheimer's disease and diabetes, supported by in-silico study.

Methods: The synthesis was initiated by the reaction of 4-methyl-1,3-thiazol-2-amine (1) with bromoacetyl bromide (2) in aqueous basic medium to obtain an electrophile,2-bromo-N-(4-methyl-1,3-thiazol-2-yl)acetamide (3). In parallel reactions, a series of carboxylic acids, 4a-r, were converted through a sequence of three steps, into respective 1,3,4-oxadiazole heterocyclic cores, 7a-r, to utilize as nucleophiles. Finally, the designed molecules, 8a-r, were synthesized by coupling 7a-r individually with 3 in an aprotic polar solvent. The structures of these bi-heterocycles were elucidated by infrared (IR), electron ionization-mass spectrometry (EI-MS), proton nuclear magnetic resonance (¹H-NMR) and carbon nuclear magnetic resonance (¹³C-NMR). To evaluate their enzyme inhibitory potential, 8a-r were screened against acetylcholinesterase (AChE), but brine shrimp lethality bioassay.

Results: The most active compound against AChE was 8l with half-maximal inhibitory concentration (IC₅₀) of 17.25 ± 0.07 µM. Against BChE, the highest inhibitory effect was shown by 8k (56.23 ± 0.09 µM). Compound 8f (161.26 ± 0.23μM) was recognized as a fairly good inhibitor of urease. In view of its inhibition of α-glucosidase, 8o (57.35 ± 0.17μM) was considered a potential therapeutic agent.

Conclusion: The results indicate that some of the synthesized products with low toxicity exhibit notable enzyme inhibitory activity against selected enzymes compared with the reference drug, and therefore, are of potential therapeutic interest

Keywords: 4-Methyl-1,3-thiazol-2-amine,1,3,4-Oxadiazole, Cholinesterases, ^5;-Glucosidase, Urease, Brine shrimp