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Synthesis, Characterization, Antibacterial Activity, and Computer-Aided Design of Novel Quinazolin-2,4-dione Derivatives as Potential Inhibitors Against Vibrio cholerae.

ABSTRACT: Cholera is a bacterial disease featured by dehydration and severe diarrhea. It is mainly caused by alimentary infection with Vibrio cholerae. Due to the wide applicability of quinazolin-2,4-dione compounds in medicinal and pharmaceutical chemistry, a new series of N-containing heterocyclic compounds was synthesized. We used the in silico docking method to test the efficacy of quinazolin-2,4-dione compounds in the prevention of cholera in humans. The newly synthesized compounds showed strong interactions and good binding affinity to outer membrane protein OmpU. Moreover, the pharmacokinetic properties of the newly synthesized compounds, such as absorption, distribution, metabolic, excretion, and toxicity (ADMET), were predicted through in silico methods. Compounds with acceptable pharmacokinetic properties were tested as novel ligand molecules. The synthesized compounds were evaluated in vitro for their antibacterial activity properties against Gram-negative Escherichia coli O78 strain using the minimum inhibition concentration (MIC) method. Compounds 2 and 6 showed reproducible, effective antibacterial activity. Hence, our study concludes that the quinazolin-2,4-dione derivatives 1 to 8 may be used as promising drug candidates with potential value for the treatment of cholera disease.

SUBMITTER: El-Naggar M

PROVIDER: S-EPMC6945456 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Synthesis, Characterization, Antibacterial Activity, and Computer-Aided Design of Novel Quinazolin-2,4-dione Derivatives as Potential Inhibitors Against Vibrio cholerae.

El-Naggar Mohamed M Mohamed Mahmoud Eldeeb ME Mosallam Ahmed Mohamed AM Salem Wesam W Rashdan Huda Rm HR Abdelmonsef Aboubakr Haredi AH

Evolutionary bioinformatics online 20200106

Cholera is a bacterial disease featured by dehydration and severe diarrhea. It is mainly caused by alimentary infection with Vibrio cholerae. Due to the wide applicability of quinazolin-2,4-dione compounds in medicinal and pharmaceutical chemistry, a new series of N-containing heterocyclic compounds was synthesized. We used the in silico docking method to test the efficacy of quinazolin-2,4-dione compounds in the prevention of cholera in humans. The newly synthesized compoun ...[more]

PMID: 31933518

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Project description:ContextAntioxidants are known to play a beneficial role in human health. Caffeic acid has been previously recognized as efficient in this context. However, such a capability can be enhanced through structural modification. Thus, 3829 caffeic acid derivatives were computational designed to that purpose by adding functional groups (-OH, -SH, -OCH3, -COOCH3, -F, -CF3, and -N(CH3)(C2H5)) to its framework. Promising candidates were chosen considering drug-like behavior, toxicity, and synthetic accessibility. The best candidates, dCAF-2, dCAF-16, and dCAF-82, were identified by comparison with reference antioxidants. The thermochemistry and kinetics of their reaction with •OOH are provided. The global rate coefficients were estimated to be 1.76 × 109 M-1 s-1, 3.19 × 109 M-1 s-1, and 1.79 × 109 M-1 s-1 in aqueous solution for dCAF-2, dCAF-16, and dCAF-82, respectively. In lipid medium, their total rate coefficients were estimated to be 3.65 × 103 M-1 s-1, 3.73 × 103 M-1 s-1, and 8.63 × 104 M-1 s-1 for dCAF-2, dCAF-16, and dCAF-82, respectively. These values allow predicting the designed caffeic acid derivatives as excellent antioxidants in both environments. The reaction forces for the main reaction path of the dCAF-2, dCAF-16, and dCAF-82 reactions with •OOH were explored.MethodsThree protocols were used: (i) CADMA-Chem (computer-assisted design of multifunctional antioxidants, based on chemical properties) to quantify ADME (absorption, distribution, metabolism, and excretion) properties, toxicity and synthetic accessibility; (ii) eH-DAMA (electron and hydrogen donating ability map) tool, to identify the derivatives expected to behave as the best antioxidants; (iii) QM-ORSA (quantum mechanics-based test for overall free radical scavenging activity), to calculate the rate constants. Electronic structure calculations were performed with Gaussian 09, at the M05-2X/6-311 + g(d,p) level of theory. Both aqueous and lipid environments were considered using the SMD continuous solvation model. Intrinsic reaction coordinate (IRC) calculations, as implemented in Gaussian 09, were used to obtain the reaction force.

Dataset Information

Synthesis, Characterization, Antibacterial Activity, and Computer-Aided Design of Novel Quinazolin-2,4-dione Derivatives as Potential Inhibitors Against Vibrio cholerae.

Publications

Synthesis, Characterization, Antibacterial Activity, and Computer-Aided Design of Novel Quinazolin-2,4-dione Derivatives as Potential Inhibitors Against <i>Vibrio cholerae</i>.

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