Aminoindoles, a novel scaffold with potent activity against Plasmodium falciparum

Barker, R. H. Jr. and Urgaonkar, S. and Mazitschek, R. and Celatka, C. and Skerlj, R. and Cortese, J. F. and Tyndall, E. and Liu, H. and Cromwell, M. and Sidhu, A. B. and Guerrero-Bravo, J. E. and Crespo-Llado, K. N. and Serrano, A. E. and Lin, J. W. and Janse, C. J. and Khan, S. M. and Duraisingh, M. and Coleman, B. I. and Angulo-Barturen, I. and Jimenez-Diaz, M. B. and Magan, N. and Gomez, V. and Ferrer, S. and Martinez, M. S. and Wittlin, S. and Papastogiannidis, P. and O'Shea, T. and Klinger, J. D. and Bree, M. and Lee, E. and Levine, M. and Wiegand, R. C. and Munoz, B. and Wirth, D. F. and Clardy, J. and Bathurst, I. and Sybertz, E.. (2011) Aminoindoles, a novel scaffold with potent activity against Plasmodium falciparum. Antimicrobial agents and chemotherapy, 55 (6). pp. 2612-2622.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/47142/

Downloads: Statistics Overview


This study characterizes aminoindole molecules that are analogs of Genz-644442. Genz-644442 was identified as a hit in a screen of ~70,000 compounds in the Broad Institute's small-molecule library and the ICCB-L compound collection at Harvard Medical School. Genz-644442 is a potent inhibitor of Plasmodium falciparum in vitro (50% inhibitory concentrations [ICs], 200 to 285 nM) and inhibits P. berghei in vivo with an efficacy of > 99% in an adapted version of Peters' 4-day suppressive test (W. Peters, Ann. Trop. Med. Parasitol. 69:155-171, 1975). Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for in vitro potency against P. falciparum and for in vitro absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with ICs of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with ICs of 28 to 65 nM against P. falciparum in vitro. In the 4-day P. berghei model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against P. falciparum blood stages in a human-engrafted NOD-scid mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observable-adverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using in vitro ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC against P. falciparum for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with >2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of in vitro culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 Mar 2017 15:05
Deposited On:23 Mar 2017 15:05

Repository Staff Only: item control page