“The most fruitful basis for the discovery of a new drug is to start with an old drug”- Sir James Black, Nobel Laureate in Physiology and Medicine said. Natural products have inspired the discovery of new drugs. Combretastatin A-4 (CA-4) is a natural product that has led to the discovery of several tubulin polymerization inhibitors. As our interest of medicinal chemistry research on anticancer drug discovery, in the present study, 2-aminoimidazole with carbonyl linker as key scaffold was considered as replacement of the double bond of CA-4. Other important pharmacophoric features like 3,4,5-trimethoxy substitution on the ring A, relevant substituted aryl as ring B , cis configuration between rings A and B and an additional linker like carbonyl group to provide the optimal dihedral angle for binding at the colchicine binding site were also considered in the design of novel 2-aminoimidazole-bridged analogs. A new and efficient approach for the synthesis of 4-aryl-5-aroyl substituted 2-aminoimidazoles via previously unknown formal diamination of guanidine with α-bromoalkene has been developed. Utilizing this method, 2-aminoimidazole analogs with relevant substitutions, were synthesized. Most of the compounds were found to exhibit pronounced antiproliferative activities in nanomolar concentrations. Compared to CA-4, they were also found to be significantly potent in tubulin polymerization inhibition. Single crystal X-ray analysis confirmed the required geometry/orientation present in the structure. The details of development of synthetic method, mechanistic aspects, biological activities and SAR will be presented.

Creating new from clinical agents: Discovery of Combretastatin A-4 inspired heterocycles as antitubulin anticancer agents

253rd National Meeting (2017)

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