Homology modeling, docking, and ADMET studies of benzoheterocyclic 4-aminoquinolines analogs as inhibitors of Plasmodium falciparum .

OBJECTIVES: The ongoing fight against endemic diseases is necessary due to the growing resistance of malarial parasites to widely accessible medications. Thus, there has been an ongoing search for antimalarial medications with improved efficacy. The goal of this study was to develop derivatives of benzoheterocyclic 4-aminoquinolines with enhanced activities and better binding affinities than the original compounds.

METHODS: Thirty-four derivatives of benzoheterocyclic 4-aminoquinolines were docked (using a model of dihydrofolate reductase-thymidylate synthase [DRTS] protein) with Molegro software to identify the compound with the minimum docking score as a design template. The generated quantitative structure-activity model was employed to estimate the activity of the designed derivatives. The derivatives were also docked to determine the most stable derivatives. Furthermore, the designed derivatives were tested for their drug-likeness and pharmacokinetic properties using SwissADME software and pkCSM web application, respectively.

RESULTS: Compound H-014, ( N -(7-chloroquinolin-4-yl)-2-(4-methylpiperazin-1-yl)-1,3-benzoxazol-5-amine) with the lowest re-rank score of -115.423 was employed as the design template. Then 10 derivatives were further designed by substituting -OH, -OCH3 , -CHO, -F, and -Cl groups at various positions of the template. We found that the designed derivatives had improved activities compared to the template. The docking scores of the designed derivatives were lower than those of the original derivatives. Derivative h-06 (7-methoxy-4-((2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-yl)amino)quinolin-6-ol) with four hydrogen bonds was identified as the most stable due to its lowest re-rank score (-163.607). While all of the designed derivatives satisfied both the Lipinski and Verber rules, some derivatives such as h-10 (cytochrome P450 1A2 [CYP1A2]); h-05, h-08, h-09, and h-10 [CYP2C19]; and h-03, h-07, h-08, and h-10 [renal organic cation transporter 2 substrate]) showed poor absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.

CONCLUSION: Ten derivatives of benzoheterocyclic 4-aminoquinolines were designed with improved efficacies. Derivatives that follow Lipinski and Verber rules and are mostly non-toxic and non-sensitive to the skin can be utilized in the development of effective antimalarial medications.