Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids

• Published in: European journal of medicinal chemistry Vol. 129; pp. 175 - 185
• Main Authors: Maurya, Shiv Shyam, Khan, Shabana I., Bahuguna, Aparna, Kumar, Deepak, Rawat, Diwan S.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 31.03.2017; Elsevier
• Subjects: Aminoquinoline; Aminoquinolines - chemistry; Aminoquinolines - pharmacology; Animals; Antimalarial activity; Antimalarials - chemical synthesis; Antimalarials - metabolism; Antimalarials - pharmacology; Binding Sites; Cell Line; Chemistry, Medicinal; Docking studies; Heme - metabolism; Heme binding activity; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Multienzyme Complexes - metabolism; Pharmacology & Pharmacy; Plasmodium falciparum - drug effects; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - metabolism; Thymidylate Synthase - metabolism; Aminoquinoline; Docking studies; Heme binding activity; Antimalarial activity; RETAIN ACTIVITY; ANALOGS; DRUGS; RESISTANCE; IMPROVED IN-VITRO; CHLOROQUINE; BETA-HEMATIN FORMATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.02.024

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. [Display omitted] •A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids was synthesized.•Antimalarial activity against both CQ-sensitive strain (D6) and CQ-resistant (W2) strain was evaluated.•Effective binding with heme in 1:1 complex.•Investigated molecular docking studies and ADMET properties.