In silico and In vitro Determination of Antiproliferative Activity of Series N-Pyrrolyl Hydrazide-Hydrazones and Evaluation of their Effects on Isolated Rat Mycrosomes and Hepatocytes

Background: The significant increase in patients suffering from different types of cancer, guides scientists to take prompt measures in the development of novel and effective antiproliferative agents, where the intercalation of heterocyclic fragments in the designed molecules has proven to be a useful practice. Objective: The newly synthesized compounds were obtained from the corresponding 1,4-dicarbonyl derivative through multicomponent reactions to produce biologically active target molecules and assessed by in silico and in vitro assays for their possible antitumor activity. Methods: The pharmacological bioassay was conducted in the panel of human tumor cell lines (i) SKW-3 (ACC 53) – human T-cell leukemia and (ii) HL-60 (ACC 3) - human acute myeloid leukemia (AML). The statistical processing of MTT data included the paired Student’s t-test with p ≤ 0.05 set as significance level. Results: All evaluated structures displayed a higher cytotoxic effect against the acute myeloid leukemia HL-60 with 11o and 11p as the most active compared to the activity against SKW-3 cell line. Throughout the cytotoxicity screening two molecules, 11l and 12o, displayed comparable chemosensitivity on both cell lines. The corresponding hepatotoxicity on isolated rat hepatocytes and microsomes was also established, identifying 11, 12 and 12a as the least toxic and 11x, 11d, 12x and 12d as the most toxic derivatives. Conclusion: As the most promising compound is underlined ethyl 1-(2-(2-((1-acetyl-1H-indol-3-yl)methylene)hydrazinyl)-2- oxoethyl)-5-(4-bromophenyl)-2-methyl-1H-pyrrole-3-carboxylate (11l) demonstrating highest activity on both evaluated tumor cell lines, decreased hepatotoxicity on all evaluated parameters and docking score of -7.517 kcal/mol.