Quantitative Structure-Activity Relationship, Structure-based Design, and ADMET studies of pyrimethamine and cycloguanil analogs inhibitors of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS).

The increasing resistance of the malarial parasite to readily available drugs ensures a continuous battle against endemic diseases. Hence, the search for antimalarial drugs with enhanced activity against the P. falciparum strain becomes an endless one. The objective of this study is to use structure-based approaches to create pyrimethamine and cycloguanil derivatives with improved activity and better docking capabilities against the Plasmodium fal-ciparum dihydrofolate reductase mutants (PfDHFR-TS). These start with the docking of the 41 data analogs of pyrimethamine and cycloguanil using Molegro Virtual Docker (MVD) to produce compound C-04, {1-(4-chlor-ophenyl)-6-(4-phenoxyphenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine}. Compound C-04, with the lowest re -rank score of-113.748 kcal/mol, was chosen as the template from which eleven (11) of its derivatives were created by substituting-NH2,-NO2, and-OH at various positions of the template to increase the number of hydrogen bonds formed. The previously constructed QSAR model was used to determine the activities of the designed derivatives. The derivatives were then subjected to molecular docking tests to find out their affinity for the PfDHFR-TS target. The activities of the designed derivatives and their docking scores were discovered to be superior to those of the template. In addition, the docking simulations of the eleven designed derivatives of the template yield derivative A-04, 6-(4-(2-aminophenoxy)-3-nitrophenyl)-1-(4-chlorophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine, with the lowest re-rank score (-128.458 kcal/mol) as the most stable designed ligand for binding with PfDHFR-TS target. The designed derivatives all met the Lipinski rule of five, except for derivatives A-04, A-09, and A-10, which do not inhibit CYP1A2 substrates, besides derivatives A-04, A-06, A-07, A-08, and A-10, which do not inhibit CYPexcept for2C19 substrates, other derivatives exhibit favorable pharmacokinetic features.