title: Synthesis and in vitro evaluation of novel 8-aminoquinoline-pyrazolopyrimidine hybrids as potent antimalarial agents.
abstract: In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5-10nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.
authors: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India; Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
authors: Murugan
authors: M
authors: Kannan
authors: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
authors: Anandkumar V
authors: AV
authors: Raichurkar
authors: Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India. Electronic address: Nawaz_f@yahoo.co.in.
authors: Fazlur Rahman Nawaz
authors: FR
authors: Khan
authors: Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India. Electronic address: Praviniyer@yahoo.com.
authors: Pravin S
authors: PS
authors: Iyer
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D062105:Molecular Docking Simulation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D011720:Pyrazoles; D011743:Pyrimidines; C080436:8-aminoquinoline
keywords: 8-Aminoquinoline; Hybridization; Plasmodium falciparum; Pyrazolopyrimidine; Structure activity relationship