title: Synthesis of novel alpha-pyranochalcones and pyrazoline derivatives as Plasmodium falciparum growth inhibitors.
abstract: Both the lack of a credible malaria vaccine and the emergence and spread of parasites resistant to most of the clinically used antimalarial drugs and drug combination have aroused an imperative need to develop new drugs against malaria. In present work, alpha-pyranochalcones and pyrazoline analogs were synthesized to discover chemically diverse antimalarial leads. Compounds were tested for antimalarial activity by evaluation of the growth of malaria parasite in culture using the microtiter plate based SYBR-Green-I assay. The (E)-3-(3-(2,3,4-trimethoxyphenyl)-acryloyl)-2H-chromen-2-one (Ga6) turned out to be the most potent analog of the series, showing IC(50) of 3.1 microg/ml against chloroquine-sensitive (3D7) strain and IC(50) of 1.1 microg/ml against chloroquine-resistant field isolate (RKL9) of Plasmodium falciparum. Cytotoxicity study of the most potent compounds was also performed against HeLa cell line using the MTT assay. All the tested compounds showed high therapeutic indices suggesting that they were selective in their action against the malaria parasite. Furthermore, docking of Ga6 into active site of falcipain enzyme revealed its predicted interactions with active site residues. This is the first instance wherein chromeno-pyrazolines have been found to be active antimalarial agents. Further exploration and optimization of this new lead could provide novel, antimalarial molecules which can ward off issues of cross-resistance to drugs like chloroquine.
authors.affiliation: Department of Pharmacy, Shri G.S. Institute of Technology and Science, Indore, MP 452003, India. gajananwanare@gmail.com
authors.forename: Gajanan
authors.initials: G
authors.lastname: Wanare
authors.forename: Rahul
authors.initials: R
authors.lastname: Aher
authors.forename: Neha
authors.initials: N
authors.lastname: Kawathekar
authors.forename: Ravi
authors.initials: R
authors.lastname: Ranjan
authors.forename: Naveen Kumar
authors.initials: NK
authors.lastname: Kaushik
authors.forename: Dinkar
authors.initials: D
authors.lastname: Sahal
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D047188:Chalcones; D011720:Pyrazoles; D003546:Cysteine Endopeptidases; C099607:falcipain