Computer-aided design, synthesis, and characterization of molecular hybrids of dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones as potential inhibitors of the penicillin-binding protein 3 (PBP-3) of Escherichia coli
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Jun 15, 2021
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Abstract
A computer-assisted approach was used to model and study privileged heterocyclic scaffolds containing dihydropyrazole, pyrimidin-2-amine, and thiazolidin-4-one moieties (hybrid pharmacophores) to obtain novel and promising antimicrobial prototype molecules. Main bioavailability descriptors were determined in order to assess the drug-likeness of the designed compounds and to pre-filter eleven compounds exhibiting the best profiles, thus passing to molecular docking study against a key penicillin-binding protein type-3 from enterotoxygenic E. coli. Seven structures were chosen by their
energies of affinity and docking interactions with key residues in the active site of the receptor. Seven compounds with the highest docking scores belonging to the series of chalcones, dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones were prepared via condensation or cyclocondensation reactions. The structural elucidation of the final products was carried out by infrared spectra analysis and NMR experiments. Such molecular hybrids considered as potential hits in the search for new antibacterial compounds will be tested in vitro in further studies.
Keywords
PBP-3 inhibitors, hybrid pharmacophores, in silico screening, dihydropyrazoles, pyrimidin-2-amines, thiazolidin-4-ones
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doi: 10.1016/s0140-6736(13)60844-2
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doi: 10.1097/QCO.0b013e32834a8b8b
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[11] Marovac J. Investigación y desarrollo de nuevos medicamentos: de la molécula al farmaco. Revista médica de Chile, 129 (1): 99-106, 2001.
doi: 10.4067/S0034-98872001000100015
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[16] Sauvage E, Derouaux A, Fraipont C, Joris MHR. et al. Crystal Structure of Penicillin-Binding Protein 3 (PBP3) from Escherichia coli. PLoS ONE. 9(5): e98042, 2014.
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doi: 10.1016/j.ejmech.2014.06.033
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doi: 10.1016/j.bmcl.2011.10.059
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doi: 10.1016/j.jsps.2011.09.007
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doi: 10.1016/j.ejmech.2011.07.007
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doi: 10.1016/j.ejmech.2013.10.004
[29] Spring D. Diversity-oriented synthesis; a challenge for synthetic chemists. Org. Biomol. Chem. 1: 3867-3870, 2003.
doi: 10.1039/B310752N
[30] Moreno-Díaz H, Villalobos-Molina R, Ortiz-Andrade R, Díaz-Coutiño D, Medina-Franco JL, Webster SP, et al. Bioorg. Med. Chem. Lett. 18: 2871–2877, 2008.
doi: 10.1016/j.bmcl.2008.03.086
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doi: 10.1016/j.bmcl.2006.05.082
[32] Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, et al. admetSAR: A Comprehensive Source and Free Tool for Assessment. J. Chem. Inf. Model. 52: 3099-3105, 2012.
doi: 10.1021/ci300367a
[33] Sashidhara KV, Rosaiah JN, Kumar A. Synth. Commun. 39: 13, 2288-2296, 2009.
doi: 10.1080/00397910802654724
[34] Hodge H, Sterner J. Am. Ind. Hyg. Assoc. Q. 10: 94-97, 1949.
[35] Durst HD, Gokel GW. Química Orgánica Experimental. Reverté S.A., Barcelona, España, pp 325-327, 1985.
[36] Jawale DV, Pratap UR, Bhosale MR, Mane RA. J. Het. Chem. 53: 1626-1630, 2016.
doi: 10.1002/jhet.673
[37] Qiya Z, Hong XH, Suhui W, Shuajiang T, Liangce R. Synth. Commun. 39: 516-522, 2009.
doi: 10.1080/00397910802399932
How to Cite
Orozco-Lopez, F., Guerrero-Villalobos, L. R., & Cuervo-Prado, P. A. (2021). Computer-aided design, synthesis, and characterization of molecular hybrids of dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones as potential inhibitors of the penicillin-binding protein 3 (PBP-3) of Escherichia coli. Universitas Scientiarum, 26(1), 17–35. https://doi.org/10.11144/Javeriana.SC26-1.cads
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Química Orgánica / Organic Chemistry / Química Orgânica
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