An efficient p‐TSA catalyzed synthesis of some new substituted‐(5‐hydroxy‐3‐phenylisoxazol‐4‐yl)‐1,3‐dimethyl‐1H‐chromeno[2,3‐d]pyrimidine‐2,4(3H,5H)‐dione/3,3‐dimethyl‐2H‐xanthen‐1(9H)‐one scaffolds and evaluation of their pharmacological and computational investigations

• Published in: Journal of molecular structure 2022-11, Vol.1267, p.133587, Article 133587
• Main Authors: Sukanya, S H, Venkatesh, Talavara, Aditya Rao, S J, Pandith, Anup
• Format: Article
• Language: English
• Subjects: Absorption; Anti-TB; Cytotoxicity; in silico molecular docking and Computational study; Isoxazole derivatives; SAR
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.133587

•Novel substituted-(5-hydroxy-3-phenylisoxazol-4-yl)-1,3-dimethyl-1H-chromeno[2,3-d] pyrimidine-2,4(3H,5H)-dione/3,3-dimethyl-2H-xanthen-1(9H)-one derivatives have been developed and spectroscopically characterised by UV-Visible, IR, 1D, 2D NMR, HRMS and P-XRD.•In vitro cytotoxicity was done by MTT assay using MCF-7 (Breast cancer) cell line.•Anti-mycobacterial activity was done by micro plate Alamar Blue assay (MABA) against Mycobacterium tuberculosis strain.•SAR, in silico molecular docking and molecular dynamics (MD) simulation studies were evaluated.•FMOs, Global reactivity parameters, MEP and CFDs were studied by DFT method. We have developed an easy and efficient protocol for the synthesis of a series of some novel substituted-(5-hydroxy-3-phenylisoxazol-4-yl)-1,3-dimethyl-1H-chromeno[2,3-d]pyrimidine-2,4(3H,5H)-dione/3,3-dimethyl-2H-xanthen-1(9H)-one derivatives (4a–j) via p-TSA catalyzed reaction of 1,3-dimethylbarbituric acid/dimedone, substituted salicylaldehyde/2-hydroxy-nepthaldehyde and 3-phenyl-5-isoxazolone was administered in refluxed temperature in the presence of aqueous ethanol. All the obtained compounds were evaluated for their therapeutic effect using pharmacological and computational investigations, and structures were confirmed using analytical and spectroscopic techniques. Absorption spectra were recorded in six different solvents such as polar protic, polar aprotic, and nonpolar solvents, λmax of all the compounds are appeared at bathochromic shift towards the longer wavelength due to the π-π* & n-π* transitions. The results of pharmacological investigations revealed that the compounds 4c, 4e, and 4h possess excellent cytotoxicity efficacy, and compounds 4c, 4d, 4h, and 4i have shown better anti-TB efficiency. The SAR study shows the importance of the electron-withdrawing group and additional phenyl nucleus enhancing the biological potency of the compounds. The results of the in silico molecular docking studies revealed that the compounds 4c and 4h effectively interacted with P38 MAP kinase (-10.9 kcal/mol) and InhA-Enoyl-Acyl Carrier Protein Reductase (-11.0 kcal/mol), respectively. Further, the molecular dynamics (MD) simulation studies revealed that the compounds 4c and 4h stabilized the macromolecular structures in terms of RMSD, RMSF, the Radius of gyration, and SASA compared to their unbound and standard compound bound structures. DFT study suggested that the compounds are chemically and biologically more reactive due to les