Design, Synthesis, and Evaluation of Imidazole Derivatives as Potential Antimalarial Drugs

A highly effective approach has been proposed for the synthesis of unique imidazole aniline compounds via a reaction sequence including acylation of substituted anilines with 2-chloroacetyl chloride, alkylation of 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde with the resulting 2-chloroacetanilides, and con­densa­tion of 2-(2-butyl-5-chloro-4-formyl-1H-imidazol-1-yl)-N-(substituted phenyl)acetamides with 4-{4-[5-(amino­methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one. The newly synthesized compounds have been screened for their in vitro antimalarial potential against Plasmodium falciparum and found to exhibit incredibly impressive half-maximum inhibitory concentration (IC₅₀) values. Molecular docking has been performed for the most active compound and dihydrofolate reductase–thymidylate synthase (DHFR-TS) from the wild-type Plasmodium falciparum, and hydrogen bond interactions between the amino acid residues Ser167 and Ser111 and azomethine and imidazole nitrogen atoms, respectively, have been revealed.