In-silico Evaluation of Phenylpiperazinyl Derivatives as Inhibitors of P. falciparum Dihydrofolate Reductase-Thymidylate Synthase: A Potential New Antimalarial Drug Candidate

Abstract

<title>Abstract</title> Resistance to antifolates targeting dihydrofolate reductase (DHFR) in <italic>Plasmodium falciparum </italic>poses a significant challenge to malarial control initiatives, with some standard drugs active chemical compounds exhibiting associated toxicity concerns. It becomes expedient to explore new antifolate inhibitors for malaria control. Herein, hypothetical compound <bold>A1</bold> (piperazine-1,4-diylbis(phenylmethanone) and it's modified mono- and di-alcohol derivatives <bold>A2</bold> and <bold>A3</bold> were screened virtually for toxicity and inhibitory efficiencies against bifunctional DHFR-thymylate protease enzyme to obtain a safer and potent antimalarial drug compound. Additionally, the physicochemical properties, drug-likeness, toxicity and binding energy of these compounds were compared with ten standard reference antimalaria drugs using Molinspiration, SwissADME, Protox II webserver and PyRx 0.8 AutoDock Vina Wizard including Discovery Studio 2020 respectively. Compounds A1, A2 and A3 were found to be non-toxic, competing favourably with nine of the standard reference existing drugs each unfortunately showing some level of immunotoxicity. Interestingly, compound <bold>A1</bold> exhibited comparable inhibitory activity with Artesunate (binding score of -9.20 kcal/mol) towards amino acid residues Ala₁₆, Leu₄₀, and Ser₁₀₈, responsible for DHFR's reduction to tetrahydrofolate reductase (THFR). Similarly, <bold>A2</bold> and<bold> A3</bold> showed binding scores of (-8.8 kcal/mol) and (-8.2 kcal/mol) respectively, both higher against DHFR-TS enzyme compared to Mefloquine at (-7.9 kcal/mol) as the only screened standard reference displaying non-toxicity against human cells. Furthermore, the three hypothetical compounds <bold>A1-3</bold> obeyed the rule of five and exhibited high gastrointestinal absorption indicative of good drug-like properties and ease of absorption by the body. Density functional theory (DFT) studies revealed a binding trend which is a function of electron affinity (EA) and electronic chemical potential (<italic>µ</italic>) values which were complementary to the binding energy trend against <italic>P. falciparum</italic> DHFR where <bold>A1</bold> exhibits the highest binding energy and <bold>A3</bold> has better pharmacokinetic properties. The results obtained from this study showed that the investigated compounds, particularly <bold>A1 and A3</bold>, can be explored as potential non-toxic candidates for antimalarial drugs development.