Novel Pyrimidinone Linked 1,2,3-Triazole Scaffolds as Anti-Microbial and Antioxidant Agents: Synthesis, In-vitro and In-silico Studies

The present study states the synthesis of a novel series of pyrimidinone linked 1,2,3-triazole scaffolds by click chemistry method. Further, the synthesized compounds were evaluated for their antimicrobial studies against S. aureus and S. pneumoniae. Among the synthesized compounds, almost all compounds demonstrated significant antimicrobial activity against S. aureus, S. pneumoniae, E.coli and P. aeruginosa, as evident from the zone of inhibition resulted. In addition, synthesised compounds were screened for their antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay method. Furthermore, computational study was performed to understand the interactions between synthesised compounds with dehydrosqualene synthase of Staphylococcus aureus (PDB ID: 2ZCS) and few Compound revealed the highest binding energies ΔG = -9.5, -9.8, and -10.1 Kcal/mol.

Synthesis of Biologically Active Novel Indole Fused Heterocyclic Derivatives: Molecular Modeling Studies

A novel series of fluoro/methoxy indole analogues 6 was synthesized and the final targets were confirmed by IR, 1H & 13C NMR and mass spectral analysis. Novel 3-substituted indole derivatives estimate for their antibacterial, antioxidant activities particularly the parent core combined with benzamides ring significantly. From antibacterial activities, compounds 6c, 6e and 6b show the highest bacterial activity against S. epidermidis, S. aureus, E. coli, with zone of inhibition 34, 30, 28 mm, respectively. Novel fluoroindole derivatives 6c, 6b, 6i shows an excellent antioxidant activity with % of inhibition 150.12, 139.04, 137.08 mmol/mL, respectively. The calculations for ligand-protein flexible of crystal structure of C(30) carotenoid dehydrosqualene synthase from S. aureus complexed with bisphosphonate BPH-700 (2ZCS). Among the designed compounds 6c exhibited highest hydrogen bonding interactions 2.06 Å, 1.85 Å with amino acids Asp27, Lys273 and binding energy -6.38 kcal/ mol, respectively. Fluoroindoles 6i, 6e and 6f shows highest ΔG = -7.90, -7.66, -7.47 kcal/mol with dissociation constants 10.32, 21.77, 22.68 μM and amino acid Lys273 interactions.

Design, Synthesis and Molecular Docking Studies of Novel Pyrazole Benzimidazole Derivatives as Potent Antibacterial Agents

A novel series of pyrazole benzimidazole derivatives were synthesized and the structure of the final targets 4a-h were confirmed by IR, Mass, 13C NMR and 1H NMR spectral analysis. The new pyrazole core with imidazole and benzimidazoles derivatives were evaluated for in vitro antibacterial, antifungal activity against six bacterial strains significantly. In dispersion, 4c, 4f and 4g had the highest antibacterial activities on these microorganisms Bacillus subtilis B29, Escherichia coli E266, with zone of inhibition 21, 19 and 19 mm, respectively. Compounds 4a, 4c, 4h shows good antifungal activity against A. niger, Fusarium oxysporum fungal strains. Further, molecular docking for protein ligands interactions was performed using the crystal structure of C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus complexed with bisphosphonate BPH-700. Among the final compounds 4e, 4g and 4h show highest binding energy ΔG = -7.89, -7.48 and -7.08 Kcal/mol, respectively and amino acid interactions Lys273, Asp27.

Cp2ZrCl2: AN EFFICIENT CATALYST FOR MULTICOMPONENT SYNTHESIS OF CAROTENOID DEHYDROSQUALENE SYNTHASE INHIBITING PYRANO[2,3-d]PYRIMIDINEDIONES

Objectives: The present protocol deals with zirconocene dichloride (Cp2ZrCl2) catalyzed synthesis of pyrano[2,3-d]pyrimidinediones through one-pot multicomponent reactions of aromatic aldehydes with malononitrile and barbituric acid at ambient temperature. All the synthesized compounds were characterized and evaluated for antibacterial, antifungal, and antioxidant activities. Furthermore, a molecular docking was carried out to reveal the atomic insights between synthesized compounds and carotenoid dehydrosqualene synthase (PDB ID: 3ACX). Methods: All the synthesized compounds were evaluated for their in vitro antimicrobial activity by diffusion method. Antioxidant activities such as 1,1-diphenyl-2-picrylhydrazyl and radical scavenging activity. A mixture of barbituric acid 1 (1 mmol), malononitrile 2 (1 mmol), benzaldehyde 3a (1 mmol), ethanol (5 mL), and Cp2ZrCl2 (5 mol %) was stirred at ambient temperature for specified time. After completion of reaction as indicated by thin-layer chromatography, the obtained crude product was filtered and purified by column chromatography on silica gel (Merck, 60–120 mesh) using ethyl acetate:pet. ether to afford pure product which was then characterized by spectroscopic methods such by FTIR, nuclear magnetic resonance (1H NMR), 13C NMR, and mass spectroscopy. Results: All the synthesized pyrano[2,3-d]pyrimidinediones were characterized by spectroscopic analysis. The results revealed that pyrano[2,3-d] pyrimidinediones (4 a-k) displayed the zone of inhibition in the range of 3–13 mm. The most active compound 4b displayed largest zone of inhibition of 13 mm for Escherichia coli (NCIM-2832) and 9 mm for Bacillus subtilis (NCIM-2635). The antifungal and antioxidant activity of all synthesized pyrano[2,3-d]pyrimidinediones (4a-k) showed moderate to good activity. Molecular docking studies suggest that pyrano[2,3-d]pyrimidinediones might inhibit the carotenoid dehydrosqualene synthase activity. Conclusion: All the synthesized pyrano[2,3-d]pyrimidinediones display moderate to good antibacterial, antifungal, and antioxidant activity. This molecular docking studies supported that pyrano[2,3-d]pyrimidinediones might inhibit the carotenoid dehydrosqualene synthase (PDB ID: 3ACX).

3D-MOLECULAR SCREENING OF DIKETOPIPERAZINE DERIVATES ON Staphylococcus aureus DEHYDROSQUALENE SYNTHASE USING VINA

Dehydrosqualene synthase enzyme has been used as protein target model for exploring docking simulation of pyrazoline analogues. One of diketopiperazine derivates that have similar structure to pyrazoline has antibacterial activity against Staphylococcus aureus (S. aureus). Vina is AutoDock- improved program that capable for molecular screening based on free-energy and binding conformation prediction between ligand and protein target. The aim of these studies is to screen diketopiperazine derivates on dehydrosqualene synthase of S. aureus using Vina. Diketopiperazine derivates, curcumin analogues, curcumin, pentagammavunon derivates (PGV-0 and PGV-1) were calculated for their geometry optimization energy using Gaussian-Density Functional Theory method. 3D-optimized ligands along with reference ligands were screened for their binding energy with dehydrosqualene synthase (2ZCO) by docking using Vina. The lowest values of binding energy were analyzed with statistic method. The results showed that top thirteen ligands of docking binding energy with receptor are diketopiperazine derivates (31%), curcumin analogues (31%), and reference ligands (38%). The new compounds of diketopiperazine derivates and curcumin analogues have better potency of binding energy than curcurmin as lead compound. Keywords: diketopiperazine, Vina, docking, Staphylococcus aureus, curcumin.

EXPLORING 3D MOLECULAR STUDIES OF DIKETOPIPERAZINE ANALOGUES ON Staphylococcus aureus DEHYDROSQUALENE SYNTHASE USING GLIDE-XP

There is a strong correlation between 3D molecular docking result with dehydrosqualene synthase protein and antibacterial activity against Staphylococcus aureus (S. aureus) of the pyrazoline analogues. The enzyme has been known as important protein for the synthesis of staphyloxanthin in S. aureus. Diketopiperazine analogues have similar structure to pyrazoline. Glide-XP, Schrodinger application that seeks for molecular docking screening between ligand and protein target is designed for speed, efficiency, and accuracy to conduct discovery efforts. The research report the three-dimension molecular studies diketopiperazine analogues for their antibacterial activity on dehydrosqualene synthase of S. aureus using Glide-XP. Analogues compound of diketopiperazine and curcumin has been calculated their geometry optimization using Gaussian-Density Functional Theory method. These 3D-optimized ligands along with reference ligands obtained from bindingDB database, MIMICs fingerprint shape screening and the compound from previous research were performed on dehydrosqualene synthase (2ZCO) for their docking score. The lowest values docking score were analyzed with multiple linear regressions. The results suggest that the diketopiperazine framework is a prospective template for modification and optimization to accomplish better potency of antibacterial activity in laboratory testing. Keywords: diketopiperazine, Glide-XP, docking score, Staphylococcus aureus, multiple linear regression.