title: Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides.
abstract: Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: David M
authors: DM
authors: Floyd
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: Philip
authors: P
authors: Stein
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: Zheng
authors: Z
authors: Wang
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: Jian
authors: J
authors: Liu
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: Steve
authors: S
authors: Castro
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Julie A
authors: JA
authors: Clark
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Michele
authors: M
authors: Connelly
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Fangyi
authors: F
authors: Zhu
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Gloria
authors: G
authors: Holbrook
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Amy
authors: A
authors: Matheny
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Martina S
authors: MS
authors: Sigal
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: Jaeki
authors: J
authors: Min
authors: Syngene International Ltd. , Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore, India 560 099.
authors: Rajkumar
authors: R
authors: Dhinakaran
authors: Syngene International Ltd. , Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore, India 560 099.
authors: Senthil
authors: S
authors: Krishnan
authors: Syngene International Ltd. , Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore, India 560 099.
authors: Sridevi
authors: S
authors: Bashyum
authors: Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey , 610 Taylor Road, Piscataway, New Jersey 08854 United States.
authors: Spencer
authors: S
authors: Knapp
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105 United States.
authors: R Kiplin
authors: RK
authors: Guy
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D018920:Coculture Techniques; D004912:Erythrocytes / Q000166:cytology / Q000469:parasitology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000962:Antimalarials; D007546:Isoquinolines; C000621125:N-(3-cyano-4-fluorophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide