Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

Abstract

New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis ( Mtb) inosine 5'-monophosphate dehydrogenase 2 ( MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure-activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis.

Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

“…The validation of GuaB2 as a new TB drug target stimulated further studies aiming at the discovery of hit compounds with bactericidal activity [38,39]; indeed, on the basis of previous published results [40][41][42][43][44], an expansion of the structure-activity relationship of benzoxazole-based derivatives revealed potent inhibitors of MTB GuaB2 displaying a Ki of 14 nM, though with a moderate antibacterial activity [39].…”

Discovery of 6‐Arylurea‐2‐arylbenzoxazole and 6‐Arylurea‐2‐arylbenzimidazole Derivatives as Angiogenesis Inhibitors: Design, Synthesis and in vitro Biological Evaluation

“…[75] Briefly,c ancer cells were grown to log phase in RPMI 1640 medium supplemented with 10 %f etal bovine serum. [75] Briefly,c ancer cells were grown to log phase in RPMI 1640 medium supplemented with 10 %f etal bovine serum.…”

“…[75] The embryos of unhatched eggs from specific-pathogen-free chickens were placed laterally in an incubator (37 8C, relative humidity: 57 %). [75] The embryos of unhatched eggs from specific-pathogen-free chickens were placed laterally in an incubator (37 8C, relative humidity: 57 %).…”

“…In vitro MTT assay for antiproliferative activity:T he antiproliferative activities of the prepared 6-amide-2-arylbenzoxazole and 6amide-2-arylbenzimidazole derivatives against HUVECs or cancer cells (H1975, A549, and HeLa) were evaluated by MTT assay,a sd escribed previously by us. [75] Briefly,c ancer cells were grown to log phase in RPMI 1640 medium supplemented with 10 %f etal bovine serum. After diluting to 2 10 4 cells mL À1 with the complete medium, 100 mL of the obtained cell suspension was added to each well of 96-well culture plates.…”

“…Chick chorioallantoic membrane (CAM) assay:C AM assays were performed according to previously published methods. [75] The embryos of unhatched eggs from specific-pathogen-free chickens were placed laterally in an incubator (37 8C, relative humidity: 57 %). On day 5o ft he incubation period, ac old light bulb was used to detect the dead eggs, which were then removed.…”