Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

Abstract

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity

“…The organic phase was dried over Na 2 SO 4 , filtered and concentrated under vacuum. 13 (25). To a solution of compound 21 (0.088 mmol) in dry N-Ndimethylformamide (0.7 ml), K 2 CO 3 (0.177 mmol) and ethyl chloroacetate (0.088 mmol) were added.…”

“…Off-white foam. 1 13 Compound 24 was dissolved in tetrahydrofuran/ethanol (1:1.5 ml) and 1N NaOH was added dropwise. The reaction was refluxed for 30 min.…”

“…The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic phase was dried over Na 2 SO 4 , filtered and concentrated under vacuum, affording compound 25 (13) Synthesis of dibenzyl(4-(4-(4-trifluoromethyl)benzamido)-1,2,5oxadiazol-3-yl)phenylphosphate (28). Compound 21 (0.143 mmol) was dissolved in dry acetonitrile (1 ml) under nitrogen atmosphere and the solution was cooled to -10˚C.…”

“…Melting points were determined on a Buchi Melting Point B540 instrument (Buchi, Flawil, Switzerland). 1 H-, 13 C-and 19 F-NMR spectra were recorded at room temperature on a Varian 300 MHz Oxford instrument (Varian, Palo Alto, CA, USA), using TMS as internal standard. CDCl 3 , CD 3 OD, acetone-d 6 and DMSO-d 6 were used as deuterated solvents for all the spectra run.…”

Synthesis and Antimicrobial Evaluation of Novel Chiral 2‐Amino‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine Derivatives

“…[7 -9] Actually, the strategies directed towards targets absent in humans are considered one of the most appealing approaches to disclose new drugs potentially safer for humans. [10][11][12][13] Moreover, it is important to underline that the thienopyridine pharmacophore strongly interfered with other microbial proteins, such as dihydrofolate reductase, secreted aspartic protease and N-myristoyl transferase from Candida albicans, dihydrofolate reductase and gyrase B from Staphylococcus aureus. [14] The increasing multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria strains worldwide, together with the lack of new effective drugs in the last decades, [15] suggested the urgent need for the identification of innovative antimicrobial targets and inhibitors.…”