Synthesis of pyrazole acrylic acid based oxadiazole and amide derivatives as antimalarial and anticancer agents

Abstract

Depravity of malaria in terms of morbidity and mortality in human beings makes it a major health issue in tropical and subtropical areas of the globe. Drug counterfeiting and non-adherence to the treatment regimen have significantly contributed to development and spread of multidrug resistance that has highlighted the need for development of novel and more efficient antimalarial drugs. Complexity associated with cancer disease and prevalence of diversified cell populations vindicates highly specific treatment options for treatment of cancer. Resistance to these anticancer agents has posed a great hindrance in successful treatment of cancer. Pondering this ongoing situation, it was speculated to develop novel compounds targeting malaria and cancer. Moving on the same aisle, we synthesized pyrazole acrylic acid based oxadiazole and amide derivatives using multi-step reaction pathways (6a-x; 6a'-h'). Schizont maturation inhibition assay was employed to determine antimalarial potential. Compound 6v emerged as the most potent antimalarial agent targeting falcipain-2 enzyme. Anticancer activity was done using sulforhodamine B assay. Compounds 6b' and 6g' demonstrated promising results against all the tested cell lines. Further, Microscopic view clearly indicated formation of apoptotic bodies, chromatin condensation, shrinkage of cells and bleb formation. Validation of the results was achieved using molecular docking studies. From the obtained results, it was observed that cyclization (oxadiazole) favored antimalarial activity while non-cyclized compounds (amides) emerged as better anticancer agents.

Keywords: 1,3,4-Oxadiazole; Amide; Cancer; Malaria; Pyrazole acrylic acids.