Exploiting the potential of aryl acetamide derived Zn(ii) complexes in medicinal chemistry: synthesis, structural analysis, assessment of biological profile and molecular docking studies

Abstract

In the medical arena, advancements in the rational design of metal-based therapeutic agents showcase increasingly significant research attempts towards the development of new compounds with fewer toxic side effects. In this context, our present manuscript explicitly encapsulates the design and synthesis of Zn(II) complexes derived from different aryl acetamides, as potential frontline enzyme inhibitors as well as antileishmanial and anticancer agents. The structures of synthesized metal complexes were established on the basis of spectro-analytical data and, in case of 4c, by single crystal X-ray diffraction analysis. The X-ray structure of Zn(II) complex, dichlorido-bis[N-(4-methoxyphenyl)acetamide-O]-zinc(II), 4c, showed the zinc atom and the chlorido ligands to lie on a mirror plane with the acetamide ligands in general positions. The coordination geometry of the zinc atom was tetrahedral with the N-(4-methoxyphenyl)acetamide ligands bound to zinc via the acetamide oxygens. The designed coordination complexes were analysed for their enzyme inhibition potential, anticancer and antileishmanial efficacy. Detailed kinetics studies for complex 4b, the most active carbonic anhydrase and alkaline phosphatase inhibitor, indicated a competitive and uncompetitive mode of inhibition against carbonic anhydrase and tissue non-specific alkaline phosphatase, respectively. The bioactivity results and molecular docking analysis revealed that the synthesized coordination complexes (4a-c) hold great potential to be developed as promising enzyme inhibitors in addition to the anticancer and anti-parasitic drug candidates. disorders. 1 In this quest, several coordination compounds have been synthesized involving different metal center like copper, zinc, cobalt, nickel, gold and antimony. 2,3 In addition, a variety of mononuclear metal complexes with different ligands have been shown to be effective for cancer therapy both in vitro and in vivo. 4-8 Transition metal complexes with platinum, gold, palladium and ruthenium metal centers are under various stages of clinical trials. 9,10 Interest in zinc complexes stems from their wide and increasing utility in medicinal chemistry. In addition, zinc is considered as the most abundant trace intracellular element with its substantial occurrence in the nucleus. 11 Furthermore, Zn(II) ions are present in zinc finger proteins that recognize and bind to DNA. 12,13 Several Zn(II) and other metal complexes with a variety of ligands have been reported in the literature with different coordination modes displaying a unique spectrum of biological functions including antitumor, antioxidant, xanthine oxidase, anticonvulsant, antimicrobial and antileishmanicidal activities. 14 Also, various metal complexes with different coordination ligands have emerged as inhibitors of carbonic anhydrases, 15 cholinesterase, 16 and alkaline phosphatases. 17 However, there is still an unmet need for the development of coordination complexes with unique and multifaceted biological profile.Hence, a combination of all com...

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