Design, Synthesis, In‐silico Studies and Antiproliferative Evaluation of Novel Indazole Derivatives as Small Molecule Inhibitors of B‐Raf

Abstract

B‐Raf, a proto‐oncogene that encodes the B‐Raf protein in the Ras/Raf/Mek/Erk (MAPK) pathway, is important in directing cell development and differentiation, mutation of which results in various types of cancers. A series of novel indazole derivatives were synthesized employing scaffold‐based approach and characterized by the spectral data. All the synthesized compounds were subjected to molecular docking to assess their binding affinity with the protein. The physicochemical and pharmacokinetic profile of the compounds revealed their compliance with Lipinski's rule. The antiproliferative capacity of the synthesized derivatives was assessed by screening them against the human melanoma cell lines Skmel‐23 and A375, which express B‐Raf in wild‐type and mutant forms, respectively. Compounds with 2‐chloro and 2‐cyano‐4‐isoproxy substitutions elicited potent inhibition against melanoma cell lines with IC50 values of 40.11 and 13.37 μM against Skmel‐23 and 16.89, 15.57 μM against A375 cells respectively. The compounds manifested greater potential than the standard doxorubicin. In order to detect changes in cell morphology and evaluate their apoptotic potential; these substances were subjected to morphological screening. Both cell lines were shown to be strongly inhibited by the 2‐cyano‐4‐isoproxy substituted indazole derivative; making it a prospective therapeutic candidate for targeting both wild‐type and mutant B‐Raf forms.