Discovery of potent and selective inhibitors ofToxoplasma gondiithymidylate synthase for opportunistic infections.
Infection by the parasiteToxoplasma gondii(tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis inT. gondii, and represents a potential target to combatT. gondiiinfection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9H-pyrimido[4,5-b]indoles1-3with single-digit nanomolar Kifor tgTS, two of which,2and3, are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Nilesh
N
Zaware
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511, United States.
Hitesh
H
Sharma
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Jie
J
Yang
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Ravi Kumar Vyas
RK
Devambatla
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Sherry F
SF
Queener
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511, United States.
Karen S
KS
Anderson
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Aleem
A
Gangjee
Active-site inhibitors; Crystal structure; Opportunistic infection; Thymidylate-synthase inhibitors; Toxoplasma gondii