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Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.


ABSTRACT: We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.

SUBMITTER: Kraus JM 

PROVIDER: S-EPMC2877169 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.

Kraus James M JM   Tatipaka Hari Babu HB   McGuffin Sarah A SA   Chennamaneni Naveen Kumar NK   Karimi Mandana M   Arif Jenifer J   Verlinde Christophe L M J CL   Buckner Frederick S FS   Gelb Michael H MH  

Journal of medicinal chemistry 20100501 10


We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing  ...[more]

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