Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase.
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.
Istituto di Chimica Organica, Facoltà di Farmacia, Università di Milano, Via Venezian 21, 20133, Milan, Italy.
Francesca
F
Clerici
Maria Luisa
ML
Gelmi
Kohei
K
Yokoyama
Donato
D
Pocar
Wesley C
WC
Van Voorhis
Frederick S
FS
Buckner
Michael H
MH
Gelb
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D051231:Farnesyltranstransferase; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
D013844:Thiazoles; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase