In vivo evaluation of novel synthetic pyrazolones as CDK9 inhibitors with enhanced pharmacokinetic properties

Aim: The structural optimization of our recently reported CDK9 inhibitor to furnish novel aminopyrazolones and methylpyrazolones with improved pharmacokinetics. Materials & methods: The synthesis of the targeted compounds was accomplished via conventional, grinding and microwave-assisted processes. The cytotoxicity of them was assayed against three carcinomas. Results: Analogs 2, 4 and 6 showed significant cytotoxicity and selectivity toward all tested cells. They also displayed potent CDK9 inhibition. Compound 6 arrested MCF-7 cycle at G2/M phase by stimulating the apoptotic pathway. The in vivo biodistribution of radiolabeled compound 6 displayed a potent targeting capability of 131I in solid tumors. Conclusion: Entity 6 is a potent CDK9 inhibitor where 131I-compound 6 can be used as a significant radiopharmaceutical imaging tool for tumors. Structural optimization of diaminopyrazole to furnish novel aminopyrazolones and methylpyrazolones with improved pharmacokinetic properties. Three compounds 2, 4 and 6 showed significant cytotoxic activity and selectivity toward all tested cancerous cells. Compounds 2, 4 and 6 also displayed potent CDK9 inhibition with an IC50 range equal to 0.496–7.149 μM. The most effective CDK9 inhibitor 6 arrested the cell cycle of MCF-7 at the G2/M phase by stimulating the apoptotic pathway. In vivo biodistribution study of 131I-6 displayed a potent targeting ability of 131I in solid tumor suggesting that 131I-6 might be used as a promising radiopharmaceutical imaging agent for cancer.