In-silico Design of Aryl and Aralkyl Amine-Based Triazolopyrimidine Derivatives with Enhanced Activity Against Resistant
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ORIGINAL ARTICLE
In‑silico Design of Aryl and Aralkyl Amine‑Based Triazolopyrimidine Derivatives with Enhanced Activity Against Resistant Plasmodium falciparum Zakari Ya’u Ibrahim1 · Adamu Uzairu1 · Gideon Shallangwa1 · Stephen Abechi1 Received: 3 August 2020 / Accepted: 30 October 2020 © The Author(s) 2020
Abstract A blend of genetic algorithm with multiple linear regression (GA-MLR) method was utilized in generating a quantitative structure–activity relationship (QSAR) model on the antimalarial activity of aryl and aralkyl amine-based triazolopyrimidine derivatives. The structures of derivatives were optimized using density functional theory (DFT) DFT/B3LYP/6–31 + G* basis set to generate their molecular descriptors, where two (2) predictive models were developed with the aid of these descriptors. The model with an excellent statistical parameters; high coefficient of determination ( R2) = 0.8884, cross-validated R2 (Q2cv) = 0.8317 and highest external validated R 2 (R2pred) = 0.7019 was selected as the best model. The model generated was validated through internal (leave-one-out (LOO) cross-validation), external test set, and Y-randomization test. These parameters are indicators of robustness, excellent prediction, and validity of the selected model. The most relevant descriptor to the antimalarial activity in the model was found to be GATS6p (Geary autocorrelation—lag 6/weighted by polarizabilities), in the model due to its highest mean effect. The descriptor (GATS6p) was significant in the in-silico design of sixteen (16) derivatives of aryl and aralkyl amine-based triazolopyrimidine adopting compound DSM191 with the highest activity (pEC50 = 7.1805) as the design template. The design compound D8 was found to be the most active compound due to its superior hypothetical activity (pEC50 = 8.9545). Keywords In silico design · QSAR · Aryl and aralkyl amine-based triazolopyrimidine · Plasmodium falciparum · GA-MLR
1 Introduction Despite decades of efforts to curb and eradicate the malaria pandemic, it still retains its status as one of the most dangerous and fatal infections in the tropical and subtropical endemic countries, having over 500 million reported cases with approximately one million deaths yearly [1]. The disease is caused by Plasmodium falciparum (P. falciparum), the most lethal of all the five Plasmodium species, others are; Plasmodium malariae (P. malariae), Plasmodium knowlesi (P. knowlesi), Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), and Plasmodium ovale (P. ovale) [2–4]. The protozoan parasite Plasmodium falciparum produced in the red blood cell (RBCs) requires various hosts for * Zakari Ya’u Ibrahim [email protected] 1
Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B 1045, Zaria, Nigeria
its growth and survival. The host is unable to manufacture purine rings de novo, hence purine is reclaimed from the host by the parasite [5]. Within the digestive vacuole of the parasite, the hemoglobin releases heme molecule
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