A quantum mechanics and molecular mechanics study of bis-thiosemicarbazones with strong antiplasmodial properties as Fe(iii)-selective chelators and inhibitors of hemozoin formation

Abstract

Inhibition of intraerythrocytic iron uptake by plasmodium parasites is a viable alternative antimalarial mode of action to that adopted by artemisinins, since microorganisms require iron for growth and replication, but this has received less research attention. Against this backdrop, an in silico study on bis-thiosemicarbazones (TSCs) with significant antiplasmodial properties as Fe(III)-selective chelators and inhibitors of hemozoin formation is undertaken herein using density functional theory (DFT), molecular docking and molecular dynamics (MD) simulations. From the large contrasts in calculated binding energies for Fe(III) and Fe(II) sequestration in aqueous solution at DSD-BLYP/def2-TZVPD level of theory (−1162.99 to −1187.64 kcal mol⁻¹ and −671.75 to −687.60 kcal mol⁻¹, respectively), the TSCs are potential Fe(III)-selective chelators as desired for chelation therapy. Based on their satisfactory oral bioavailability profiles, the TSCs are found to be adequately drug-like. They are therefore expected to easily penetrate parasitized erythrocytes and inhibit the growth/development of plasmodium parasites by scavenging and externalizing intraerythrocytic ferric iron. Moreover, docking and adsorption studies of these TSCs onto the (001) face of the β-hematin crystal have yielded favorable binding free energies (−9.874 to −11.83 kcal mol⁻¹) and negative adsorption energies (−84.61 to −109.80 kcal mol⁻¹), respectively. The adsorption energies obtained herein are either comparable or more negative than those obtained in previous studies for well-known antimalarial drugs. Therefore, besides Fe(III)–chelation, the antiplasmodial activities of the TSCs studied are also attributable to inhibition of β-hematin/hemozoin formation, which has a cascade effect on plasmodium parasite survival. From our findings, in vitro β-hematin inhibition assays on these TSCs are recommended.