Novel indeno-pyrazole and indeno-pyrimidine conjugates: Synthesis, DFT, anticancer screening and in silico studies as potent tubulin inhibitors

Background: A leading procedure for creating innovative anticancer treatments that, in theory, can address many of the pharmacokinetic drawbacks of conventional anticancer medications is hybrid drug design. Lately, many researchers have reported that various indeno-pyrazole and indeno-pyrimidine conjugates have important anticancer activity. Tubulin polymerization, crucial for cell motility and proliferation, is a key target for anticancer drugs. Cytotoxic medications prevent tubulin polymerization, essential for chemotherapy. Objectives: The approach and goal of this work include combining two bioactive substances, such as pyrazole or pyrimidine, with indanone in a compact structure for synergism, and evaluating the produced compounds as anticancer medicines, based on the previously reported promising properties. It would be expected that activity against anticancer cell lines would be impressive. Methods: The enone moiety of 2-arylidene-1,3-indandiones was swapped out for five or six membered heterocycles as pyrazoles, pyrimidines, and pyrimidine hybrids to get fourteen target compounds. Using the LDH assay, ten of the novel synthesized compounds were investigated in vitro for their effects on human cancer cells HCT116, HepG2, and MCF-7, as well as one human healthy cell line (BJ-1). Computational investigations were performed to highlight the structure-activity relationship (SAR) and ascertain the likely interactions between the newly synthetic compounds and the tubulin colchicine-binding site (PDB ID: 1SA0). Moreover, density-functional theory (DFT) and topological investigations such as ELF and RDG were performed for the two promising liver anticancer candidates (9 and 10) to identify the primary binding sites and weak interactions within the molecules. Results: All screened ten compounds can be considered good human colon and breast anticancer candidate drugs. While two compounds, (9 and 10), are good human liver anticancer candidates (IC50 = 2.8 +/- 0.1 and 2.7 +/- 0.1, respectively) compared to Doxorubicin (IC50 = 4.8 +/- 0.5 mu M). The docking score of compound 9, which is greater than colchicine's (S= -6.77 kcal/mol), was -7.48 kcal/mol. Compound 10 outperformed the other compounds and colchicine in terms of binding affinity docking score (-8.56 kcal/mol). Conclusion: Based on encouraging anticancer activity, docking studies, and their favorable interaction with tubulin, the title compounds (9 and 10) appear to be a viable anticancer therapeutic candidates.