Molecular modeling and design of some β-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives against chloroquine sensitive, 3D7 strain of Plasmodium falciparum

Resistance nature of Plasmodium falciparum (P. falciparum) to the most effective antimalarial drug, Artemisinin, intimidate the global goal of total eradication of malarial. In an attempt to overcome this challenge, the research was aimed at designing derivatives of β-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles with improve activity against the P. falciparum through structural modifications of the most active compound (design template), and their activity determined using the developed theoretical predictive model. To achieve this, the geometries were optimized via density functional theory (DFT) using B3LYP/6-31G(∗) basis set to generate molecular descriptors for model development. Analysis of the developed model and the descriptors mean effect lead to the design of derivatives with improved activity. Five (5) theoretical models were developed, where the model {pIC(50) = 5.95067(SpMin5_Bhi) - 0.0323461(RDF45m) + 0.0203865 (RDF95e) + 0.0499285 (L1m) - 3.50822} with the highest coefficient of determination (R(2)) of 0.9367, cross-validated R(2) (Q(2)cv) of 0.8242, and the external validated R(2) (R(2)(pred)) of 0.9462, selected as the best model. The mean effect analysis revealed descriptor SpMin5_Bhi as the most contributive. The descriptor encodes the first ionization potentials of the compounds and are influenced by electron-withdrawing/donating substituents. Hence, structural modifications of the compound with the highest activity (a design template) using electron-withdrawing substituents such as –NO(2), –SO(3)H, -Br, –I, –CH(2)CH(3), and –CH(3) was done at a different positions, to obtain five (5) hypothetical novel compounds. The statistical results, shows the robustness, excellent prediction power, and validity of the selected model. Descriptor analysis revealed the first ionization potential (SpMin5_Bhi) to play a significant role in the activity of β-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives. The five design derivatives of β-amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles with higher activities revealed compound 21C to have an antimalarial activity of pIC(50) = 6.7573 higher than it co-designed compounds and even the standard drug. This claim could be verified through molecular docking to determine their interaction with the target protein.