Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase

Francesca Clerici; Maria Luisa Gelmi; Kohei Yokoyama; Donato Pocar; Wesley C Van Voorhis; Frederick S Buckner; Michael H Gelb

doi:10.1016/s0960-894x(02)00338-4

Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase

Bioorg Med Chem Lett. 2002 Aug 19;12(16):2217-20. doi: 10.1016/s0960-894x(02)00338-4.

Authors

Francesca Clerici¹, Maria Luisa Gelmi, Kohei Yokoyama, Donato Pocar, Wesley C Van Voorhis, Frederick S Buckner, Michael H Gelb

Affiliation

¹ Istituto di Chimica Organica, Facoltà di Farmacia, Università di Milano, Via Venezian 21, 20133, Milan, Italy.

PMID: 12127541
DOI: 10.1016/s0960-894x(02)00338-4

Abstract

A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC(50) of 2 microM and blocked the growth of the bloodstream parasite in vitro with an ED(50) of 10 microM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / metabolism
Animals
Farnesyltranstransferase
Inhibitory Concentration 50
Molecular Structure
Rats
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology*
Trypanosoma brucei brucei / drug effects*
Trypanosoma brucei brucei / enzymology*
Trypanosoma brucei brucei / growth & development

Substances

Thiazoles
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I
Farnesyltranstransferase