Design, Synthesis, Molecular Docking, and ADME-Tox Investigations of Imidazo[1,2-a]Pyrimidines Derivatives As Antimicrobial Agents

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Nov 9

PMID 39519699

Authors

Djamila Benzenine

Ismail Daoud

Nadia Aissaoui

Zahira Kibou

Julio A Seijas

M Pilar Vazquez-Tato

Chewki Ziani-Cherif

Lahcen Belarbi

Noureddine Choukchou-Braham

Affiliations

Soon will be listed here.

Abstract

A convenient and effective synthesis of imidazo[1,2-]pyrimidine derivatives has been developed under microwave irradiations using AlO as a catalyst in solvent-free conditions. The functionalized imidazo[1,2-]pyrimidine derivatives are useful in biochemistry and medical science. In our investigation, the antimicrobial activity of the synthesized compounds was evaluated against 13 microorganisms, including 6 Gram-positive bacteria, 4 Gram-negative bacteria, and 3 pathogenic fungi. Bioactivity tests revealed that the majority of the compounds exhibited good antimicrobial activity. Finally, molecular docking simulations and ADME-T predictions were performed, showing that the most active compounds have good binding modes with microbial targets and promising pharmacokinetic safety profiles.

References

Kumar G, Kiran Tudu A . Tackling multidrug-resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors. Bioorg Med Chem. 2023; 80:117187. DOI: 10.1016/j.bmc.2023.117187. View

Bajda M, Wieckowska A, Hebda M, Guzior N, Sotriffer C, Malawska B . Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci. 2013; 14(3):5608-32. PMC: 3634507. DOI: 10.3390/ijms14035608. View

Kibou Z, Aissaoui N, Daoud I, Seijas J, Vazquez-Tato M, Klouche Khelil N . Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies. Molecules. 2022; 27(11). PMC: 9182143. DOI: 10.3390/molecules27113439. View

Imberty A, HARDMAN K, CARVER J, Perez S . Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A. Glycobiology. 1991; 1(6):631-42. DOI: 10.1093/glycob/1.6.631. View

Rai N, Narayanaswamy V, Govender T, Manuprasad B, Shashikanth S, Arunachalam P . Design, synthesis, characterization, and antibacterial activity of {5-chloro-2-[(3-substitutedphenyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones. Eur J Med Chem. 2010; 45(6):2677-82. DOI: 10.1016/j.ejmech.2010.02.021. View

Aeluri R, Alla M, Polepalli S, Jain N . Synthesis and antiproliferative activity of imidazo[1,2-a]pyrimidine Mannich bases. Eur J Med Chem. 2015; 100:18-23. DOI: 10.1016/j.ejmech.2015.05.037. View

Stewart J . Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model. 2007; 13(12):1173-213. PMC: 2039871. DOI: 10.1007/s00894-007-0233-4. View

Daoud I, Mesli F, Melkemi N, Ghalem S, Salah T . Discovery of potential SARS-CoV 3CL protease inhibitors from approved antiviral drugs using: virtual screening, molecular docking, pharmacophore mapping evaluation and dynamics simulation. J Biomol Struct Dyn. 2021; 40(23):12574-12591. PMC: 8459931. DOI: 10.1080/07391102.2021.1973563. View

Barakat A, Al-Majid A, Al-Qahtany B, Ali M, Teleb M, Al-Agamy M . Synthesis, antimicrobial activity, pharmacophore modeling and molecular docking studies of new pyrazole-dimedone hybrid architectures. Chem Cent J. 2018; 12(1):29. PMC: 5852137. DOI: 10.1186/s13065-018-0399-0. View

10.

Ravindar L, Hasbullah S, Rakesh K, Izzaty Hassan N . Pyrazole and pyrazoline derivatives as antimalarial agents: A key review. Eur J Pharm Sci. 2022; 183:106365. DOI: 10.1016/j.ejps.2022.106365. View

11.

Cho J, Park Y, Ahn J, Lim Y, Rhee S . Structural and functional insights into O-methyltransferase from Bacillus cereus. J Mol Biol. 2008; 382(4):987-97. DOI: 10.1016/j.jmb.2008.07.080. View

12.

Skok Z, Barancokova M, Benek O, Cruz C, Tammela P, Tomasic T . Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors. ACS Med Chem Lett. 2020; 11(12):2433-2440. PMC: 7734788. DOI: 10.1021/acsmedchemlett.0c00416. View

13.

Sindi A, Chawn M, Hernandez M, Green K, Islam M, Locher C . Anti-biofilm effects and characterisation of the hydrogen peroxide activity of a range of Western Australian honeys compared to Manuka and multifloral honeys. Sci Rep. 2019; 9(1):17666. PMC: 6881396. DOI: 10.1038/s41598-019-54217-8. View

14.

Then A, Zhang H, Ibrahim B, Schuster S . Bioinformatics Analysis of the Periodicity in Proteins with Coiled-Coil Structure-Enumerating All Decompositions of Sequence Periods. Int J Mol Sci. 2022; 23(15). PMC: 9369452. DOI: 10.3390/ijms23158692. View

15.

Azzouzi M, Ouafi Z, Azougagh O, Daoudi W, Ghazal H, El Barkany S . Design, synthesis, and computational studies of novel imidazo[1,2-]pyrimidine derivatives as potential dual inhibitors of hACE2 and spike protein for blocking SARS-CoV-2 cell entry. J Mol Struct. 2023; 1285:135525. PMC: 10080474. DOI: 10.1016/j.molstruc.2023.135525. View

16.

Pires D, Blundell T, Ascher D . pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015; 58(9):4066-72. PMC: 4434528. DOI: 10.1021/acs.jmedchem.5b00104. View

17.

Miguel A, Hsin J, Liu T, Tang G, Altman R, Huang K . Variations in the binding pocket of an inhibitor of the bacterial division protein FtsZ across genotypes and species. PLoS Comput Biol. 2015; 11(3):e1004117. PMC: 4374959. DOI: 10.1371/journal.pcbi.1004117. View

18.

Sasaki D, Fujihashi M, Okuyama N, Kobayashi Y, Noike M, Koyama T . Crystal structure of heterodimeric hexaprenyl diphosphate synthase from Micrococcus luteus B-P 26 reveals that the small subunit is directly involved in the product chain length regulation. J Biol Chem. 2010; 286(5):3729-40. PMC: 3030375. DOI: 10.1074/jbc.M110.147991. View

19.

Daina A, Michielin O, Zoete V . SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7:42717. PMC: 5335600. DOI: 10.1038/srep42717. View

20.

Raymond A, Lovell S, Lorimer D, Walchli J, Mixon M, Wallace E . Combined protein construct and synthetic gene engineering for heterologous protein expression and crystallization using Gene Composer. BMC Biotechnol. 2009; 9:37. PMC: 2680836. DOI: 10.1186/1472-6750-9-37. View