Synthesis, comparative in vitro antibacterial, antioxidant and UV fluorescence studies of bis indole Schiff bases and molecular docking with ct-DNA and SARS-CoV-2 Mpro.

In this study, synthesis of 15 novel bis indole-based Schiff bases (SBs) 4a-4o was conducted by condensation of 2-(1-aminobenzyl)benzimidazole with symmetrical bis-isatins linked via five alkyl chains (n = 2-6). These were subjected to ADME (absorption, distribution, metabolism and excretion), physiochemical properties, molecular docking, in vitro antibacterial and antioxidant studies. The in silico studies indicated lower toxicity with metabolic stability for nearly all the derivatives proving reliability as drug candidates. The comparative antibacterial study against Staphylococcus aureus and Escherichia coli, also showed a superior inhibition than reference drug and their mono counterparts. The increase in linker alkyl chain length and variation of substituents in indole, further predicted increased inhibition, with maximum value for compound 4o at 50 µg/ml. The in vitro calf thymus DNA (ct-DNA) binding ability of compounds 4c, 4f, 4i, 4l, 4 m, 4n, and 4o was evaluated via ultraviolet-visible and fluorescence spectroscopy techniques. A hyperchromic effect was observed with no apparent wavelength shift which predicted for the groove binding mode. A moderate binding constant for 4o, in fluorescence results, confirms groove binding. The molecular docking of 4o with ct-DNA (PDBID:1BNA) and SARS-CoV-2 Mpro (3CL protease, PDBID:6LU7) prove its efficacy as potential DNA binder and antiviral agent.

Design and in silico screening of aryl allyl mercaptan analogs as potential histone deacetylases (HDAC) inhibitors.

The Zn+2 HDACIs show promising anticancer activity. Allyl mercaptan (AM), a metastabilzed monomeric form of diallyl disulphide (DADS) shows better HDACI activity. The present work screens a dataset of aryl AM derivatives 1(a-g) for potential HDACI action via in silico models. DFT calculations predicted the geometrical parameters and frontier orbital calculations suggested better chemical reactivity. Negative chemical potential and NBO hyper conjugative interactions predicted their chemical stability. ADME study confirmed favourable drug likeliness. Molecular docked models suggested the formation of coordinate bond between sulphur of allylmercaptan and Zn2+ cofactor of HDAC8. Besides, models also predicted the dominance of hydrophobic interactions. The aryl AM analogs docked perfectly with HDAC3 as well. The glide score and S-Zn distance of compounds 1a, 1f and 1g were found to be better than allylmercaptan. Therefore, the designed aryl AM analogs filtered as better HDACIs. These could be further used for design and synthesis of new improved HDACIs.

Spiro-Indole-Coumarin Hybrids: Synthesis, ADME, DFT, NBO Studies and In Silico Screening through Molecular Docking on DNA G-Quadruplex.

New series of hybrids were synthesized by combination of 4-hydroxycoumarin with spiro[indol-indazole-thiazolidine]-diones and spiro[indol-pyrazole-thiazolidine]-diones, via hitherto unknown Schiff bases. The effects of substituents, such as -F, -Br and -CH3, on the crucial characteristics pertaining to the hybrids were investigated through computational studies. In silico or virtual screening through molecular docking studies on the library of 22 compounds, including reference compounds, precursors, non-hybrid and hybrid derivatives, was performed on DNA G-quadruplex of the human genome. All six freshly synthesized hybrids showed high binding energy as compared to non-hybrids as well as reference compounds. The presence of substituents at 5-position of indole enhanced the binding tendency of the ligand. ADME studies indicated good oral bioavailability and absorption of these compounds. Density Functional Theory (DFT) calculations of hybrids were done at B3LYP/6-311G++(d,p) level of computation. Their HOMO and LUMO energy plots reflected the presence of high charge transfer and chemical potential. Natural bond order (NBO) calculations predicted hyperconjugative interactions. The Molecular Electrostatic Potential (MEP) surface plots showed possible electrophilic and nucleophilic attacking sites of the hybrids. Compound 10 a (5-fluoro-spiro[indol-indazole-thiazolidine]-dione-coumarin hybrid), on the basis of global reactivity descriptors, was filtered to be chemically most reactive with the highest binding energy of -8.23 kcal/mol with DNA G-quadruplex. The synthesized hybrid coumarin derivatives in correlation with theoretical docking studies validate that hybrid derivatives are more reactive compared to their non-hybrid counterparts.

Synthesis, DFT studies, molecular docking, antimicrobial screening and UV fluorescence studies on ct-DNA for novel Schiff bases of 2-(1-aminobenzyl) benzimidazole.

Novel Schiff bases (SBs) were synthesized by condensation of 2-(1-Amino benzyl) benzimidazole with heterocyclic and aromatic carbonyl compounds. The structural characterization was done using 1H, 13C NMR, FTIR and ES-MS spectroscopic techniques. The in silico pharmacokinetics showed that nearly all compounds obeyed Lipinski rule of 5 with low toxicity and metabolic stability. The global reactivity descriptors were calculated using DFT approach. The molecular docking result of SBs with ct-DNA suggested interaction via groove binding mode. The antibacterial activity was tested against S. aureus and E. coli, indicated significant inhibition than reference drug. The compound 4d gave best results at 50 µg ml-1 concentrations. UV/Vis and Fluorescence spectroscopy tools were used to evaluate ct-DNA binding ability of compounds 4a-e through hypochromic shift. The steady state fluorescence predicted a moderate binding constant of 1.12 × 104 for 4d, indicative of non-intercalative mode.

Luminescence, circular dichroism and in silico studies of binding interaction of synthesized naphthylchalcone derivatives with bovine serum albumin.

Chalcones possess various biological properties, for example, antimicrobial, anti-inflammatory, analgesic, antimalarial, anticancer, antiprotozoal and antitubercular activity. In this study, naphthylchalcone derivatives were synthesized and characterized using 1 H NMR 13 C NMR, Fourier transform infrared and mass techniques. Yields for all derivatives were found to be >90%. Protein-drug interactions influence the absorption, distribution, metabolism and excretion (ADME) properties of a drug. Therefore, to establish whether the synthesized naphthylchalcone derivatives can be used as drugs, their binding interaction toward a serum protein (bovine serum albumin) was investigated using fluorescence, circular dichroism and molecular docking techniques under physiological conditions. Fluorescence quenching of the protein in the presence of naphthylchalcone derivatives, and other derived parameters such as association constants, number of binding sites and static quenching involving confirmed non-covalent binding interactions in the protein-ligand complex were observed. Circular dichroism clearly showed changes in the secondary structure of the protein in the presence of naphthylchalcones, indicating binding between the derivatives and the serum protein. Molecular modelling further confirmed the binding mode of naphthylchalcone derivatives in bovine serum albumin. A site-specific molecular docking study of naphthylchalcone derivatives with serum albumin showed that binding took place primarily in the aromatic low helix and then in subdomain II. The dominance of hydrophobic, hydrophilic and hydrogen bonding was clearly visible and was responsible for stabilization of the complex.