Comprehensive characterization and preclinical assessment of an imidazopyridine‐based anticancer lead molecule

Abstract

Imidazopyridine scaffold holds significant pharmacological importance in the treatment of cancer. An in‐house synthesized imidazopyridine‐based molecule was found to have promising anticancer activity against breast cancer, lung cancer, and colon cancer. The molecule is an inhibitor of pyruvate kinase M2, the enzyme that elevates tumor growth, metastasis and chemoresistance by directly controlling tumor cell metabolism. Screening of the physicochemical properties of any lead molecules is essential to avoid failure in late‐stage drug development. In this research, the physicochemical properties of the molecule including log P, log D, pKa, and plasma protein binding were assessed to check its drug‐likeness. Plasma and metabolic stability of the molecule were also evaluated. Moreover, pharmacokinetic profiles of the lead molecule in Sprague‐Dawley rats and in vitro metabolite identification studies were also performed. Finally, an in silico software, Pro‐Tox‐II, was used to predict toxicity of the molecule and its metabolites. Log P, Log D (pH 7.4), pKa, and plasma protein binding of the molecule were found to be 2.03%, 2.42%, 10.4%, and 98%, respectively. The molecule was stable in plasma and metabolic conditions. A total of nine new metabolites were identified and characterized. Cmax and t½ of this molecule were found to be 4016 ± 313.95 ng/mL and 9.57 ± 3.05 h, respectively. Based on the previously reported study and this finding, the molecule can be considered as a promising anticancer lead with potential drug‐likeness properties. Further preclinical and clinical drug discovery studies may be initiated in continuation of this study in search of a potential anticancer lead.

Adaptive space search-based molecular evolution optimization algorithm

“…In drug development, it is crucial to optimize molecules to enhance their pharmacological and bioactive properties, and weaken their unsatisfactory properties, such as toxicity and adverse reactions ( Bulbule et al 2023 , Mohammed et al 2023 ). The change of a molecule’s property is essentially bound up with the modification of its chemical structures.…”