Analogs of N′-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases

Abstract

Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppressing Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure—activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents.

Biochemical and functional characterizations of tyrosine phosphatases from pathogenic and nonpathogenic mycobacteria: indication of phenyl cyclopropyl methyl-/phenyl butenyl azoles as tyrosine phosphatase inhibitors

“…One of the ser/thr kinases, protein kinase G (PknG), which plays a role in intracellular survival of mycobacteria in the host, has recently been used to identify the inhibitor AX20017 (Scherr et al 2007). Yet, in another study, it was shown that N′-hydroxymethanimidamide inhibitors have potent activity against the two methionine aminopeptidases of Mtb (Bhat et al 2012). These compounds did not become the lead inhibitors due to poor minimum inhibitory concentrations (MICs); however, it was suggestive that with certain modifications, new series of the inhibitors can be designed.…”

Bridging of a substrate between cyclodextrin and an enzyme's active site pocket triggers a unique mode of inhibition

“…Mutational studies have shown that the MetAP gene is essential for survival in bacteria [8,9] and cell proliferation in eukaryotes [10–12]. In various reports, inhibitors of MetAPs have been identified as potential anticancer [1,13,14], antimalarial [15,16], antibacterial [17,18] and anti-obesity [19,20] drugs. Due to the fact that bacteria contain a single distinct class (Type I) of the enzyme as opposed to those present in eukaryotes (Types I and II), there has been interest in designing isozyme selective inhibitors against bacterial MetAP as desirable antibiotic agents.…”

Tricyclic thiazoles are a new class of angiogenesis inhibitors

“…During a routine test of target compounds and intermediates synthesized in our laboratory, we discovered that four tricyclic thiazoles— 3 , 7 , 9 , and 11 (Table 1)—were moderately antiproliferative against human umbilical vein endothelial cells (HUVEC) in a [ 3 H]-thymidine incorporation assay In fact, these tricyclic thiazoles had been synthesized in the course of our development of methionine aminopeptidase (MetAP) inhibitors as antimycobacterial agents. 7 It has been established earlier using fumagillin that inhibition of human MetAP2 leads to the growth inhibition of HUVEC. 8,9 However, tricyclic thiazoles 3 , 7 , 9 , and 11 did not inhibit (up to 20 μM) either isoforms of human MetAPs (hMetAP1 and hMetAP2), suggesting that HUVEC inhibition proceeded through a different mechanism.…”

“…The tricyclic thiazoles were synthesized as per our earlier procedure 7 using a variation of Hantzsch thiazole synthesis. Two typical examples are shown in Scheme 1.…”