MoS2-Calix[4]arene Catalyzed Synthesis and Molecular Docking Study of 2,4,5-Trisubstituted Imidazoles As Potent Inhibitors of Mycobacterium tuberculosis.

A MoS2-supported-calix[4]arene (MoS2-CA4) nanocatalyst was used for efficient synthesis of 2,4,5-trisubstituted imidazole derivatives from 1-(4-nitrophenyl)-2-(4-(trifluoromethyl)phenyl)ethane-1,2-dione, aldehydes and ammonium acetate under solvent-free conditions. Reusability of the catalyst up to five cycles without any significant loss in the yields of the product is the unique feature of this heterogeneous solid catalysis. Furthermore, the noteworthy highlights of this method are safe reaction profiles, broad substrate scope, excellent yields, economical, solvent-free, and simple workup conditions. All synthesized compounds were evaluated for their in vitro antitubercular (TB) activity against Mycobacterium tuberculosis (Mtb) H37Rv. Among the screened compounds 3c, 3d, 3f, 3m, and 3r had MIC values of 2.15, 2.78, 5.75, 1.36, and 0.75 µM, respectively, and exhibited more potency than the reference drugs pyrazinamide (MIC: 3.12 µM), ciprofloxacin (MIC: 4.73 µM), and ethambutol (7.61 µM). Besides, potent compounds (3c, 3d, 3f, 3m, and 3r) have been tested for inhibition of MabA (ß-ketoacyl-ACP reductase) enzyme and cytotoxic activity against mammalian Vero cell line. A molecular docking study was carried out on the MabA (PDB ID: 1UZN) enzyme to predict the interactions of the synthesized compounds. The results of the in vitro anti-TB activity and docking study showed that synthesized compounds have a strong anti-TB activity and can be adapted and produced more effectively as a lead compound.

3-oxoacyl-ACP reductase from Schistosoma japonicum: integrated in silico-in vitro strategy for discovering antischistosomal lead compounds.

BACKGROUND: Schistosomiasis is a disease caused by parasitic worms and more than 200 million people are infected worldwide. The emergence of resistance to the most commonly used drug, praziquantel (PZQ), makes the development of novel drugs an urgent task. 3-oxoacyl-ACP reductase (OAR), a key enzyme involved in the fatty acid synthesis pathway, has been identified as a potential drug target against many pathogenic organisms. However, no research on Schistosoma japonicum OAR (SjOAR) has been reported. The characterization of the SjOAR protein will provide new strategies for screening antischistosomal drugs that target SjOAR. METHODOLOGY/PRINCIPAL FINDINGS: After cloning the SjOAR gene, recombinant SjOAR protein was purified and assayed for enzymatic activity. The tertiary structure of SjOAR was obtained by homology modeling and 27 inhibitor candidates were identified from 14,400 compounds through molecular docking based on the structure. All of these compounds were confirmed to be able to bind to the SjOAR protein by BIAcore analysis. Two compounds exhibited strong antischistosomal activity and inhibitory effects on the enzymatic activity of SjOAR. In contrast, these two compounds showed relatively low toxicity towards host cells. CONCLUSIONS/SIGNIFICANCE: The work presented here shows the feasibility of isolation of new antischistosomal compounds using a combination of virtual screening and experimental validation. Based on this strategy, we successfully identified 2 compounds that target SjOAR with strong antischistosomal activity but relatively low cytotoxicity to host cells.