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Extensive Structure-Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety.

ABSTRACT: Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram-negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure-activity relationship studies are key for the in-depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possibilities for variations of the C-terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella-protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocks D and E.

SUBMITTER: Behroz I

PROVIDER: S-EPMC6972991 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Extensive Structure-Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety.

Behroz Iraj I Durkin Patrick P Grätz Stefan S Seidel Maria M Rostock Lida L Spinczyk Marcello M Weston John B JB Süssmuth Roderich D RD

Chemistry (Weinheim an der Bergstrasse, Germany) 20191211 72

Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram-negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure-activity relationship studies are key for the in-depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27 newly synthesized albicidins give profound insights into possib ...[more]

PMID: 31642561

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Project description:ContextMicro-hydration of the aminobenzoic acid is essential to understand its interaction with surrounding water molecules. Understanding the micro-hydration of the aminobenzoic acid is also essential to study its remediation from wastewater. Therefore, we explored the potential energy surfaces (PESs) of the para-aminobenzoic acid-water clusters, ABW[Formula: see text], [Formula: see text], to study the microsolvation of the aminobenzoic acid in water. In addition, we performed a quantum theory of atoms in molecules (QTAIM) analysis to identify the nature of non-covalent bondings in the aminobenzoic acid-water clusters. Furthermore, temperature effects on the stability of the located isomers have been examined. The located structures have been used to calculate the hydration free energy and the hydration enthalpy of the aminobenzoic acid using the cluster continuum solvation model. The hydration free energy and the hydration enthalpy of the aminobenzoic acid at room temperature are evaluated to be -7.0 kcal/mol and -18.1 kcal/mol, respectively. The hydration enthalpy is in perfect agreement with a previous experimental estimate. Besides, temperature effects on the calculated hydration enthalpy and free energy are reported. Finally, we calculated the gas phase binding energies of the most stable structures of the ABW[Formula: see text] clusters using twelve functionals of density functional theory (DFT), including empirical dispersion. The DFT functionals are benchmarked against the DLPNO-CCSD(T)/CBS. We have found that the three most suitable DFT functionals are classified in the following order: PW6B95D3 > MN15 > [Formula: see text]B97XD. Therefore, the PW6B95D3 functional is recommended for further study of the aminobenzoic acid-water clusters and similar systems.MethodsThe exploration started with classical molecular dynamics simulations followed by complete optimization at the PW6B95D3/def2-TZVP level of theory. Optimizations are performed using Gaussian 16 suite of codes. QTAIM analysis is performed using the AIMAll program.

Project description:The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4-6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4-6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4-6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2-6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2-6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.

Dataset Information

Extensive Structure-Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety.

Publications

Extensive Structure-Activity Relationship Study of Albicidin's C-Terminal Dipeptidic p-Aminobenzoic Acid Moiety.

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