Design, synthesis and anti-tubercular evaluation of new 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives. Part 1

A series of 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives were synthesized and evaluated for anti-tubercular activity. Among these compounds, 10d, 15, 12h and 12k inhibited Mycobacterium tuberculosis (Mtb) growth with MIC values between 1.9 and 7.7 μM and low toxicity against VERO cells. The four compounds were also tested against multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) clinical strains, which were found to show moderate activity. In addition, molecular docking simulation was performed to position compounds 10d, 15, 12h and 12k into mtFabH active site to predict the probable binding mode. These studies thus suggest that the designed 2-amino-5-phenylthiophene-3-carboxylic acid scaffold may serve as new promising template for further elaboration as anti-TB drugs.

A series of 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives (10a-m, 15, 12a–k) were designed and synthesized for anti-tubercular activity.Figure optionsDownload as PowerPoint slideHighlights
► Thiophene-3-carboxylic acid derivatives were designed for anti-tubercular activity.
► Compounds 10d, 15, 12h and 12k exhibited potent activity and low toxicity.
► The four compounds were also tested against MDR-TB and XDR-TB clinical strains.
► Docking was performed to predict binding mode between inhibitors and mtFabH.