Piperazine derivatives: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies

Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

“…Tables 1 and 2. As references, GEQ compound and its phenyl analogue 1 were firstly tested on InhA protein to confirm their activity and for comparison (Table 1). Both compounds showed a complete InhA inhibition at 50 µM and IC 50 in the nanomolar range, as expected [9,11]. Compound 1 demonstrated the most potent inhibitory activity by comparison with GEQ.…”

Functional, thermodynamics, structural and biological studies of in silico-identified inhibitors of Mycobacterium tuberculosis enoyl-ACP(CoA) reductase enzyme

“…The Labio_3, Labio_11 and inhibitors of Mt InhA (Table 1) have a carbonyl-containing linker in the form of a carboxamide (Labio_2 and Labio_16), propanamide (Labio_6), urea (Labio_3) or a hydrazone-bound carbonyl (Labio_11). The importance of a carbonyl group in a series of piperazine compounds inhibitors of Mt InhA has been discussed6. Substitution of the carbonyl group for a sulfonyl moiety resulted in a 100-fold increase in the IC 50 value, which has been proposed to be due to a reduced hydrogen-bond basicity of sulfonamide compared to amide groups6.…”

“…The importance of a carbonyl group in a series of piperazine compounds inhibitors of Mt InhA has been discussed6. Substitution of the carbonyl group for a sulfonyl moiety resulted in a 100-fold increase in the IC 50 value, which has been proposed to be due to a reduced hydrogen-bond basicity of sulfonamide compared to amide groups6. However, caution should be exercised as amide groups are also present in the chemical structure of compounds Labio_1, Labio_7, Labio_9, Labio_12, and Labio_20, which failed to show any inhibitory effect on Mt InhA enzyme activity.…”

“…This is needed as IC 50 and classical competitive, non-competitive and uncompetitive inhibition modes follow a rapid equilibrium process. Accordingly, Mt InhA (2.2 μM) was pre-incubated with inhibitor (10 μM), aliquots were taken at different times and added to the reaction mixture containing NADH (60 μM) and DD-CoA (45 μM), and initial velocity measurements were plotted as a function of time of pre-incubation6. Control experiments were carried out pre-incubating Mt InhA (2.2 μM) with DMSO (5%) in the absence of inhibitors, and initial velocity measured as a function of time of pre-incubation6.…”

“…The FAS-II system elongates acyl fatty acid precursors yielding the long carbon chain (50–60 carbons) of the meromycolate branch of mycolic acids of mycobacteria5678. Mycolics acids are high-molecular-weight α-alkyl, β-hydroxy fatty acids bound as esters to tetramycolypentaarabinosyl clusters in the cell wall6. These structures have been linked to virulence, to the ability of survival and replication of the bacillus inside macrophages, and as barrier for intracellular entry of a number of common antibiotics7.…”