1071323-12-0Relevant articles and documents
Novel amide and imidazole compounds as potent hematopoietic prostaglandin D2 synthase inhibitors
Olson, Kirk L.,Holt, Melissa C.,Ciske, Fred L.,Kramer, James B.,Heiple, Paige E.,Collins, Margaret L.,Johnson, Carrie M.,Ho, Chi S.,Morano, M. Ines,Barrett, Stephen D.
, (2021/01/19)
In seeking novel and potent small molecule hematopoietic prostaglandin D2 synthase (H-PGDS) inhibitors as potential therapies for PGD2-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole “linker” between the pyrimidine or pyridine “core” ring and the “tail” ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD2 stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.
Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata
G-Dayanandan, Narendran,Paulsen, Janet L.,Viswanathan, Kishore,Keshipeddy, Santosh,Lombardo, Michael N.,Zhou, Wangda,Lamb, Kristen M.,Sochia, Adrienne E.,Alverson, Jeremy B.,Priestley, Nigel D.,Wright, Dennis L.,Anderson, Amy C.
, p. 2643 - 2656 (2014/04/17)
Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.
