Design, Synthesis and Biological Evaluation of Novel Spiro‐[Chroman‐2,4′‐Piperidin]‐4‐One Analogs as Anti‐Tubercular Agents

Abstract

A series of novel spiro‐[chromane‐2,4′‐piperidin]‐4(3H)‐one derivatives were designed, synthesized and structures were confirmed by analytical methods, viz., 1H‐NMR, 13C‐NMR and mass spectrometry. The synthetic derivatives were evaluated for their anti‐tuberculosis (anti‐TB) activity against Mycobacterium tuberculosis (Mtb) strain H37Ra. Among all the evaluated Compounds, PS08 exhibited significant inhibition with MIC value of 3.72 μM while MIC values of the remaining Compounds ranged from 7.68 to 230.42 μM in comparison to the standard drug INH (MIC 0.09 μM). The two most active Compounds however showed acute cytotoxicity towards the human MRC‐5 lung fibroblast cell lines. The in silico ADMET profiles of the titled Compounds were predicted and found within the prescribed limits of the Lipinski and Jorgenson rules. Molecular docking study of the notably active Compound (PS08) was also carried out after performing validation in order to understand the putative binding position of the test ligand at the active site of selected target protein Mtb tyrosine phosphatase (PtpB).

Synthesis and Analytical Characterization of Cyclization Products of 3-Propargyloxy-5-benzyloxy-benzoic Acid Methyl Ester

“…Methyl 5-(benzyloxy)-2H-chromene-7-carboxylate was obtained as a side product from the cyclization of 3-(propargyloxy)-5-benzyloxy-benzoic acid methyl ester. After simultaneous deprotection of the hydroxyl group and double-bond reduction, the purified compounds were characterized by spectroscopic methods (FT-IR, 1 H and 13 C NMR, NOESY, and HSQC). HRMS analysis of the corresponding carboxylic acid was also performed to definitively confirm its identity.…”

“…Mono-and bidimensional NMR spectra were recorded at room temperature on a Varian-Mercury Oxford 300 cryomagnet (Oxford Instruments, Abingdon, UK), operating at 300 MHz for 1 H and 75 MHz for 13 C, or on a Bruker Avance 500 (Billerica, MA, USA) instrument, operating at 500 MHz for 1 H and 125 MHz for 13 C. Depending on the solubility of the compound, CDCl 3 or DMSO-d 6 were used as deuterated solvents for all spectra run. Chemicals shifts are expressed in ppm (δ) from tetramethylsilane resonance in the indicated solvents; coupling constants (J-values) are given in Hertz (Hz).…”

“…Chromane is a bicyclic scaffold, ubiquitous in a wide variety of bioactive natural products and synthetic compounds exhibiting antitumor, anti-inflammatory, antiviral, antiprotozoal, and antimicrobial effects [1][2][3][4][5][6][7][8][9][10]. Among them, some have also shown moderate-to-good antitubercular activities [11][12][13][14][15][16][17][18].…”