Title

Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors As Antimalarials

Abstract

Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays. © 2007 American Chemical Society.

Publication Date

9-20-2007

Publication Title

Journal of Medicinal Chemistry

Volume

50

Issue

19

Number of Pages

4585-4605

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm0703340

Socpus ID

34648816239 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/34648816239

This document is currently not available here.

Share

COinS