Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors

Abstract

Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code:5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using 1 H NMR, 13 C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 µg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

“…The most promising compound (18, Figure 7) displayed a 2.6-log reduction in bacterial count. Activity against active bacilli and M.tb in infected macrophages was also confirmed [175].…”

Identification of novel chemical scaffolds that inhibit the growth of Mycobacterium tuberculosis in macrophages

“…In general, PTUs were 5-10-fold more active against intracellular bacteria. To the best of our knowledge, this is the first report of these compounds as antitubercular agents although other thiourea derivatives have antitubercular activity(21–24).…”

“…To the best of our knowledge, this is the first report of these compounds as antitubercular agents although other thiourea derivatives have antitubercular activity (21)(22)(23)(24).…”

“…tuberculosis with good acitivity of IC 50 <10 µM (Table 7). Three compounds (23)(24)(25) were cyotoxic and we could not calculate activity. Three compounds (26, 27 and 29) showed good intracellular potency with IC 50 <5 μM.…”

Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

“…The (thio)urea branch is an element of several medicines with anticancer profiles, such as sorafenib, multikinase-inhibitory diarylthiorea derivative, or tenovin-1, the benzylthiourea, which acts as a reversible inhibitor of class III HDAC sirtuins (Figure 1). On the other hand, it was reported that (hetero)aryl terminal fragments of thiourea moiety, enriched with electron-negative substituents, could provide biological responses, not only cytotoxic [2][3][4], but also antibacterial [2][3][4][5][6][7][8], antiviral [2,[9][10][11][12], antimycobacterial [5,13], antioxidant [14], and anti-inflammatory [6] properties, as well as central nervous system activation [15][16][17][18].…”