In-silico guided design, synthesis and bio-evaluation of potential chemotherapeutic agents against malaria, cancer and disease-causing pathogens

Abstract

Computational-based strategies have become of great significance in drug discovery, owing to their key contributions towards the development of new therapeutics. In various diseases, the overall lack of response to existing therapeutic treatments, primarily associated with gene mutations, is the major driver of drug resistance. Therefore, this work focuses on addressing this challenge, by designing and identifying new potential bioactive hybrids, using molecular and reverse docking as prediction studies, targeting three diseases; malaria, cancer, and microbial related infections. 4(1H)-pyridone-based antimalarial, 2,5-disubstituted benzimidazole-based anticancer, and quinoxaline-6-carboxamidine-urea-based antimicrobial compounds were designed via molecular hybridization and molecular docking, synthesized through multi-step synthetic routes. Their potential inhibitors as were predicted using biological screening. A library of new 4(1H)-pyridone-containing intermediates, and target molecules were successfully synthesized. Seven of the newly synthesized compounds 2.9a, 2.9b, 2.10c, 2.11b, 2.11c, 2.12a, 2.12b screened for antimalarial activities, only target compounds 2.9a and 2.9b displayed excellent inhibitory activities (96% and 97% at 1 μM, 99% and 98% at 5 μM) against K1 CQ resistant strain (CQR) and CQ-sensitive (CQS) NF54, (Table 2.4), compared to that of CQ reference drug with an inhibitory activity of 100, both at 1 and 5 μM respectively. Other newly synthesized intermediates 2.10c, 2.11b, 2.11c, 2.12a, 2.12b gave moderate to low inhibitory P. falciparum activities. The IC50 of these target compounds 2.9a and 2.9b displayed notable anti-plasmodial activities against K1 CQ resistant strain (CQR) at 0.10 and 0.04, while at 0.13 and 0.05 against P.xxi falciparum CQ-sensitive (CQS) NF54. Single crystal structures of intermediate compounds 2.4a and 2.4b were also determined using X-ray diffraction. Molecular modelling of target compounds 2.9a and 2.9b showed binding potential of these compounds 2.9a and 2.9b, unto the Q0 binding site of the cytochrome bc1 complex and the disruption of the electron transport chain of the mitochondrial. In the second aspect of the work, as a result of remarkable anticancer activities of 2- disubstituted benzimidazole derivatives, series of 2-disubstituted benzimidazole derivatives 3.4a-e, and 3.6a-f, Scheme 3.5, were designed, using literature reports as a guide. The target molecules 3.6a-f were successfully synthesized when pyrrolidine was employed as the catalyst, ensuring the formation of final products. The synthesized compounds were tested for cytotoxicity activity against MCF-7 cell lines, but none of the target compounds, even at all concentrations (0.195-100 μg/mL), demonstrated cytotoxicity comparable to the standard drug, camptothecin, which induces cell death at 57% (at 0.08 μg/mL). As a result, the target structures were docked using reverse docking, and the most likely target compound 3.4b, gave a docking score of -9.16. Finally, in the third aspect of the work, quinoxaline-6-carboximidine target molecules 4.5a-f were successfully designed and synthesized. Out of twelve envisaged target structures, only six were successfully synthesized, which may be due to the presence of an electron-withdrawing substituent on the phenyl ring of the isocyanate. This discovery emphasizes the importance of the presence of an electron withdrawing group in the isocyanate derivatives towards the reactivity with the amidine 4.4. Successfully synthesized target compounds 4.5a-f were docked unto Escherichia coli lytic transglycosylase (PDB code: 2PIC) and beta-lactamase (PDB code: 2NZE). The molecular docking results indicated that these target structures could be important targets for the discovery and development of novel antibacterial medicinal agents.