title: Synthesis and insight into the structure-activity relationships of chalcones as antimalarial agents.
abstract: Licochalcone A (I), isolated from the roots of Chinese licorice, is the most promising antimalarial compound reported so far. In continuation of our drug discovery program, we isolated two similar chalcones, medicagenin (II) and munchiwarin (III), from  Crotalaria medicagenia , which exhibited antimalarial activity against  Plasmodium falciparum . A library of 88 chalcones were synthesized and evaluated for their in vitro antimalarial activity. Among these, 67, 68, 74, 77, and 78 exhibited good in vitro antimalarial activity against  P. falciparum  strains 3D7 and K1 with low cytotoxicity. These chalcones also showed reduction in parasitemia and increased survival time of Swiss mice infected with  Plasmodium yoelii  (strain N-67). Pharmacokinetic studies indicated that low oral bioavailability due to poor ADME properties. Molecular docking studies revealed the binding orientation of these inhibitors in active sites of falcipain-2 (FP-2) enzyme. Compounds 67, 68, and 78 showed modest inhibitory activity against the major hemoglobin degrading cysteine protease FP-2.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-226001, UP, India. t_narendra@cdri.res.in
authors.forename: Narender
authors.initials: N
authors.lastname: Tadigoppula
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Korthikunta
authors.forename: Shweta
authors.initials: S
authors.lastname: Gupta
authors.forename: Papireddy
authors.initials: P
authors.lastname: Kancharla
authors.forename: Tanvir
authors.initials: T
authors.lastname: Khaliq
authors.forename: Awakash
authors.initials: A
authors.lastname: Soni
authors.forename: Rajeev Kumar
authors.initials: RK
authors.lastname: Srivastava
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Puri
authors.forename: Kanumuri Siva Rama
authors.initials: KS
authors.lastname: Raju
authors.lastname: Wahajuddin
authors.forename: Puran Singh
authors.initials: PS
authors.lastname: Sijwali
authors.forename: Vikash
authors.initials: V
authors.lastname: Kumar
authors.forename: Imran Siddiqi
authors.initials: IS
authors.lastname: Mohammad
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020134:Catalytic Domain; D047188:Chalcones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002839:Chromans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D029864:Crotalaria / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001578:Benzopyrans; D047188:Chalcones; D002839:Chromans; D015853:Cysteine Proteinase Inhibitors; D054852:Small Molecule Libraries; D003546:Cysteine Endopeptidases; C416224:falcipain 2