Design, Synthesis and Biological Evaluation of Heterocyclic Compounds as Anticancer Agents

Abstract

Cancer is a heterogeneous group of diseases, characterized by uncontrolled growth of the malignant cell population & accounted for 9.6 million deaths all around the globe in 2018 (WHO). The present research work was started with a literature survey on cancer and the role of kinases in different cancers. The c-Met kinase was selected as a target due to its central role in tumour cell biology. In the present study, design, synthesis and pharmacological evaluation were carried out to identify novel hits as c-Met kinase inhibitors and anticancer agents. Initially, 3D-QSAR studies were performed on Class I and Class II c-Met kinase inhibitors. From Class I c-Met kinase inhibitors, a series of 1‑Sulfonylpyrazolo[4,3‑b]pyridine derivatives was selected for comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) studies. The optimum CoMFA and CoMSIA models were obtained from distill based alignment methodology and were found statistically significant with cross-validated correlation coefficients (q2 ) of 0.722 for CoMFA and 0.626 for CoMSIA. CoMFA predicted r2 pred of 0.821 and CoMSIA predicted r2 pred of 0.840 showed that the predicted values were in good agreement with the experimental values. The derived contour maps from 3D QSAR models revealed the significant structural features (steric, hydrophobic and electronic effects) required for improving c-Met kinase inhibitory activity. To further enrich designing, structural features and binding mode of reported Class I c-Met kinase inhibitors were studied and benzimidazole derivatives were designed. Docking studies, in silico pharmacokinetic and toxicity prediction studies were carried out for the designed benzimidazole derivatives and a total of 16 molecules were synthesized in Series I and 30 molecules were synthesized in Series II. For the synthesis of benzimidazole derivatives, acetylation of 5-Chloro-3-nitroaniline was carried out and the product was utilized for SNAr displacement of C-5 halogen by different N-substituted piperazines/morpholine. Further, deacetylation reaction was carried out to yield the free amine and the coupling reaction was carried out with different benzyl bromide derivatives in the presence of sodium hydride. Final designed compounds of Series I were synthesized by one-pot reduction and cyclization of N substituted nitroaniline derivative. Series II molecules were synthesized by minor modification in the synthetic methodology of scheme I. After deacetylation reaction, the 5-substituted nitroanilines were subjected to one-pot reduction and cyclization, to prepare benzimidazole derivatives. Finally, the benzimidazoles derivatives were treated with aromatic sulfonyl chlorides to obtain final products of Series II. Further, all the synthesized compounds were confirmed by spectroscopic techniques like Mass (ESI-MS), 1HNMR and 13C NMR. The purity of final compounds was determined by HPLC analysis. The synthesized benzimidazole derivatives were screened for c-Met kinase enzyme inhibition assay and in-vitro antiproliferative activity against human cancer cell lines and their structure activity relationship (SAR) studies were discussed. From the above results, the compound 279c (PKP9) from Series I and, compounds 285d(PKPS3A) and 288e (PKPS4B) from Series II were found as most potent compounds in cell based and enzyme based assays. Ligand based drug design studies and synthesis provided 1-substitued benzimidazole derivatives as c-Met kinase inhibitors and anti-cancer agents.