Design, Synthesis, and In Silico Insights of new 4‐Piperazinylquinolines as Antiproliferative Agents against NCI Renal Cancer Cell Lines

A novel series of hybrid 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3-carbonitrile derivatives has been designed, synthetized and evaluated for anticancer properties on the NCI60 panel. Strong antiproliferative effects have been detected against renal cancer cells. In vitro results were supported by in silico ADMET, docking, and molecular dynamics studies, providing insights into their mechanisms of action.

Abstract

In the search for new anticancer compounds, quinoline and piperazine moieties represent the most promising pharmacophoric fragments for the development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting in hybrid molecules with enhanced biological activity. In this study, we have developed a new series of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3-carbonitrile compounds (8 a–l), with potential anticancer effect, by combining the quinoline, the piperazinyl and the benzoylamino moieties. The rationalized compounds (8 a–l) were first evaluated in silico to assess the ADMET and drug-likeness profiles, synthesized using appropriate synthetic strategies and then tested in vitro under the National Cancer Institute DTP-NCI60 program. The entire series exhibited potent anticancer activity against the renal cell carcinoma (RCC) cell line UO-31, with compounds 8 c and 8 g effectively inhibiting cancer cell growth without excessive cytotoxic effects (growth percentages of −7 and −19, respectively). In silico induced fit docking (IFD) and molecular dynamics (MD) studies provided further insights into the putative mechanisms of action for both compounds, which were predicted to strongly bind key oncogenic proteins involved in RCC progression. The promising in vitro and in silico results herein presented provide a solid foundation for the development of a new series of small heterocyclic molecules with anticancer activity.

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