4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies

Deepak Kumar; Shabana I Khan; Babu L Tekwani; Prija Ponnan; Diwan S Rawat

doi:10.1016/j.ejmech.2014.10.061

4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies

Eur J Med Chem. 2015 Jan 7:89:490-502. doi: 10.1016/j.ejmech.2014.10.061. Epub 2014 Oct 22.

Authors

Deepak Kumar¹, Shabana I Khan², Babu L Tekwani³, Prija Ponnan¹, Diwan S Rawat⁴

Affiliations

¹ Department of Chemistry, University of Delhi, Delhi 110007, India.
² National Center for Natural Products Research, University of Mississippi, MS-38677, USA; Department of Biomolecular Sciences, University of Mississippi, MS-38677, USA; Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
³ National Center for Natural Products Research, University of Mississippi, MS-38677, USA; Department of Biomolecular Sciences, University of Mississippi, MS-38677, USA.
⁴ Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address: [email protected].

PMID: 25462261
DOI: 10.1016/j.ejmech.2014.10.061

Abstract

A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro 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. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction.

Keywords: Aminoquinoline; Antimalarial activity; Docking studies; Heme binding studies.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aminoquinolines / chemical synthesis
Aminoquinolines / chemistry
Aminoquinolines / pharmacology*
Animals
Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology*
Binding Sites
Cell Line
Heme / chemistry*
Molecular Docking Simulation*
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*

Substances

Aminoquinolines
Antimalarials
Pyrimidines
Heme
4-aminoquinoline