Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata

Abstract

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.

Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates

“…The C-ring is either attached in a meta position relative to the B-ring (compounds 1 - 7 ) or a para-position (compounds 8 - 11 ). Methods for the synthesis of compounds 1 , 2 and 6 , 7 (17), 3-5 (18) as well as 8-11 (21) have been previously published.…”

Characterization of trimethoprim resistant E. coli dihydrofolate reductase mutants by mass spectrometry and inhibition by propargyl-linked antifolates

“…Enzyme kinetic parameters and inhibition data were determined following a standard method that has been previously reported. 40 For enzymatic inhibition assays, inhibitor in DMSO was added to the enzyme–NADPH mix and allowed to incubate for 5 minutes before initiating the reaction. The inhibitor concentration and volume were based on the conditions that result in a 50% reduction in enzyme activity.…”

Synthesis, Bioactivity, Molecular Docking and POM Analyses of Novel Substituted Thieno[2,3-b]thiophenes and Related Congeners

“…All newly synthesized compounds contain large aromatic systems, exhibiting noticeable hydrophobic and Van der Waals (VDW) interactions along with few additional hydrogen bonding with the crucial residues i.e. , Ile9, Glu32, Phe36, Ile112, and Tyr118 of 4HOF ( C. albicans ) [ 27 ]. However, 3ZMI ( E. coli ) His150, Asn154, Ser201, and His254 were observed to be the hotspot residues for their inhibitory activity [ 28 ].…”