Iron(III)-Catalyzed Regioselective Synthesis of Electron-Rich Benzothiazoles from Aryl Isothiocyanates via C-H Functionalization.

We report herein a direct synthetic route for the preparation of 2-arylbenzothiazoles using aryl isothiocyanates and electron-rich arenes. The synthetic route involves triflic acid promoted addition of the arenes to aryl isothiocyanates followed by FeCl3-catalyzed C-S bond formation via C-H functionalization. The approach provides the advantage of synthesis of benzothiazoles without the conventional use of aryl aldehyde/carboxylic acid precursors employing the less expensive iron(III) catalyst.

Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues.

Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05-≤100 µg mL-1. Among these derivatives, IPA-6 (MIC 0.05 µg mL-1), IPA-9 (MIC 0.4 µg mL-1), and IPS-1 (MIC 0.4 µg mL-1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8-3.12 µg mL-1). The most active compounds with MIC of <3.125 µg mL-1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 µg mL-1).

Synthesis of new analogs of AKBA and evaluation of their anti-inflammatory activities.

A new series of 11-keto-ß-boswellic acid and 3-O-acetyl-11-keto-ß-boswellic acid analogs (5, 7, 8, 10, 13, 18a-d, 27a-c, 28a-d) were synthesized by modification of hydroxyl and acid functional moieties of boswellic acids. The structures of these analogs were confirmed by spectral data analysis (1H, 13C NMR and mass). Compounds 18b, 27a and 8 showed potent 5-lipoxygenase enzyme inhibitory activity (IC50: 19.53, 20.31 and 44.14µg/mL). The computational studies revealed that selectivity of AKBA is due to its fitment into the 5-LOX receptor, which is missing for the other enzymes like 12-LOX, COX-1 and COX-2. Our study found potentiating effects of 2-formyl and 3-keto substituents in reviving inactive AKBA analogues possessing essential COOH group at 4th position.

Synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents.

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6µg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25µg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6µg/mL) followed by H13 (6.25µg/mL) and H17 (12.5µg/mL), H19 (3.125µg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and ß-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.

Denigrins A-C: new antitubercular 3,4-diarylpyrrole alkaloids from Dendrilla nigra.

Chemical diversity is vital to antitubercular drug discovery as it ensures a novel bioactivity profile. Marine sponges have so far provided more than 1000 new bioactive molecules. Ethyl acetate extract of the marine sponge Dendrilla nigra on bioactivity-guided screening yielded three new compounds denigrins A-C, with potent antitubercular activity. Spectral and chemical analyses confirmed that these three compounds belong to the 3,4-diaryl pyrrole alkaloid category. The presence of monohydroxy substitution on benzene rings is not very common in lamellarin and related 3,4-diaryl pyrrole alkaloids isolated from marine invertebrates. Among these, denigrin C showed highest potency (minimum inhibitory concentration 4 µg/mL) against Mycobacterium tuberculosis H37Rv.