Aminoquinoline-Pyrimidine-Modified Anilines: Synthesis, In Vitro Antiplasmodial Activity, Cytotoxicity, Mechanistic Studies and ADME Predictions

作者：Tripathi Mohit; Khan Shabana I; Ponnan Prija; Kholiya Rohit; Rawat Diwan S

来源：ChemistrySelect, 2017, 2(28): 9074-9083.

DOI：10.1002/slct.201701558

• antimalarial
• aminoquinoline
• pyrimidine
• hybrid-drug
• antiplasmodial
• heme-binding
• docking studies

A series of antimalarial 4-aminoquinoline-pyrimidine hybrids incorporating modified anilines at the pyrimidine end was designed and synthesized through a facile synthetic route. The present hybrids displayed excellent equipotent invitro antiplasmodial activities against both chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of P. falciparum with up to 11-fold (IC50 = 0.033 mu M) better activity than the reference drug, (chloroquine, IC50 = 0.370 mu M) against the resistant strain. The compounds were found to be non-cytotoxic towards the mammalian cells up to the highest tested concentration. The present hybrids displayed good binding interactions with both monomeric and dimeric heme, suggesting heme-detoxification as their mechanism of action. Furthermore, the most active hybrids were found to display good in silico docking interactions within the active site of plasmodial dihydrofolate reductase (DHFR) enzyme (wild and mutant type). Computational studies predicted favorable pharmacokinetic parameters and oral drugability for the synthesized molecules.

• 出版日期2017-9-29