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20 results on '"Dhinakaran R"'

19. Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides.

Author

Floyd DM, Stein P, Wang Z, Liu J, Castro S, Clark JA, Connelly M, Zhu F, Holbrook G, Matheny A, Sigal MS, Min J, Dhinakaran R, Krishnan S, Bashyum S, Knapp S, and Guy RK

Subjects
Anilides chemical synthesis, Anilides pharmacology, Anilides toxicity, Animals, Antimalarials chemical synthesis, Antimalarials pharmacology, Antimalarials toxicity, Coculture Techniques, Erythrocytes cytology, Erythrocytes parasitology, Humans, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Isoquinolines toxicity, Mice, Microsomes, Liver metabolism, Plasmodium falciparum physiology, Solubility, Stereoisomerism, Structure-Activity Relationship, Anilides chemistry, Antimalarials chemistry, Isoquinolines chemistry, Plasmodium falciparum drug effects
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.

Published
2016
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20. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines.

Author

Le Manach C, Paquet T, Brunschwig C, Njoroge M, Han Z, Gonzàlez Cabrera D, Bashyam S, Dhinakaran R, Taylor D, Reader J, Botha M, Churchyard A, Lauterbach S, Coetzer TL, Birkholtz LM, Meister S, Winzeler EA, Waterson D, Witty MJ, Wittlin S, Jiménez-Díaz MB, Santos Martínez M, Ferrer S, Angulo-Barturen I, Street LJ, and Chibale K

Subjects
Animals, Antimalarials pharmacokinetics, Antimalarials pharmacology, Ether-A-Go-Go Potassium Channels metabolism, Humans, Liver parasitology, Malaria parasitology, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Mice, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Structure-Activity Relationship, Antimalarials chemistry, Antimalarials therapeutic use, Malaria drug therapy, Plasmodium berghei drug effects, Plasmodium falciparum drug effects, Pyrazoles chemistry, Pyrazoles therapeutic use, Pyridines chemistry, Pyridines therapeutic use
Abstract

Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.

Published
2015
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