In silico modeling of tetraoxane-8-aminoquinoline hybrids active against Plasmodium falciparum

Abstract

Background: Quantitative structure-activity relationships (QSAR) is a technique that is used to produce a model that connects biological activities of compounds to their chemical structures, and molecular docking is a technique that reveals the binding mode and interactions between a drug and its target enzyme. These techniques have been successfully applied in the design and development of many drug candidates and herein were employed to build a model that could help in the development of more potent antimalaria drugs. Results: Descriptors of the compounds were calculated using the PaDEL-Descriptor software, and Genetic Function Algorithm (GFA) was used to select descriptors and build the model. A robust and reliable model was generated and validated to have internal and external squared correlation coefficient (R 2) of 0.9622 and 0.8191, respectively, adjusted squared correlation coefficient (R adj) of 0.9471, and leave-one-out (LOO) cross-validation coefficient (Q 2 cv) of 0.9223. The model revealed that the antiplasmodial activities of 1,2,4,5-tetraoxane-8-aminoquinoline hybrids depend on MATS3m, GATS8p, GATS8i, and RDF50s descriptors. MATS3m, GATS8i, and RDF50s influenced the antiplasmodial activities of the compounds positively while GATS8p negatively with the greatest influence. The docking result shows strong interactions between 1,2,4,5-tetraoxane-8-aminoquinoline hybrids and Plasmodium falciparum lactate dehydrogenase (pfLDH) with binding affinities ranging from − 6.3 to − 10.9 kcal/mol which were better than that of chloroquine (− 6.1 kcal/mol), suggesting that these compounds could be better inhibitors of pfLDH than chloroquine. Conclusion: The results of this study could serve as a model for designing new potent 1,2,4,5-tetraoxane-8aminoquinolines with better antiplasmodial activities for the development of highly active antimalaria drugs.

In Silico Screening and Molecular Dynamics Simulation of Potential Anti-Malarial Agents from Zingiberaceae as Potential Plasmodium falciparum Lactate Dehydrogenase (PfLDH) Enzyme Inhibitors

“…This compound has the lowest binding energy score to PfLDH through hydrophobic contact. Seven sulcanal binding site residues, including Arg231(A), Ile239(A), Arg171(A), Pro184(A), Arg185(A), Ser170(A), and Glu238(A), are similar with 1,2,4,5-tetraoxane-8-aminoquinoline hybrids binding pocket in PfLDH that tested by the similar study before (Mahmud et al 2020). Sulcanal bind Arg171(A) as essential pyruvate binding residue.…”

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…When assessed in comparison to their primaquine counterparts (C‐5 unsubstituted 8‐aminoquinolines), the hybrid compounds with the C‐5 aryl on the 8‐aminoquinoline demonstrated improved metabolic persistence in microsomes without sacrificing dual phase AM activity. In 2020, Mahmud et al 264 investigated the QSAR and molecular docking of 1,2,4,5‐tetraoxane‐8‐amino‐quinoline hybrids. The structural similarity of 1,2,4,5‐tetraoxane‐8‐amino‐quinoline hybrids with P. falciparum lactate dehydrogenase ( pf LDH) is in the band of −6.3 to −10.9 × 10 3 mol/L, which is higher than the binding affinity of CQ (−6.1 × 10 3 mol/L), according to a molecular docking study.…”

Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

“…Thus, although, the World Health Organization (WHO) recommend combination therapy of classical drugs [1], new and effective medications are needed to circumvent established mechanisms of resistance. In this context, the design and synthesis of new antimalarial agents as hybrid molecules combining two or more active pharmacophoric fragments constitute an interesting strategy [5][6][7][8][9][10] for which a diversity of natural products such as taxoids, peptides, carbohydrates and steroids have been hybridized by other pharmacologically active molecules such as β-lactams, anthraquinones, C 60 -fullerenes, porphyrin and enediyne [11,12]. Four membered cyclic amides ,2-azetidinones, are commonly known as β-lactams.…”