Synthesis, in-vitro antibacterial, antifungal, and molecular modeling of potent anti-microbial agents with a combined pyrazole and thiophene pharmacophore

Yahia Nasser Mabkhot; Nahed Ahmed Kaal; Seham Alterary; Salim S Al-Showiman; Assem Barakat; Hazem A Ghabbour; Wolfgang Frey

doi:10.3390/molecules20058712

Synthesis, in-vitro antibacterial, antifungal, and molecular modeling of potent anti-microbial agents with a combined pyrazole and thiophene pharmacophore

Molecules. 2015 May 14;20(5):8712-29. doi: 10.3390/molecules20058712.

Authors

Yahia Nasser Mabkhot¹, Nahed Ahmed Kaal², Seham Alterary³, Salim S Al-Showiman³, Assem Barakat^{4

5}, Hazem A Ghabbour⁶, Wolfgang Frey⁷

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. yahia@ksu.edu.sa.
² Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. nahed.a.k@hotmail.com.
³ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. salterary@ksu.edu.sa.
⁴ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. ambarakat@ksu.edu.sa.
⁵ Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia-21321 Alexandria, Egypt. ambarakat@ksu.edu.sa.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. ghabbourh@yahoo.com.
⁷ Institut für Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, Stuttgart 70569, Germany. wolfgang.frey@oc.uni-stuttgart.de.

Abstract

Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a-c, 4, 6a-c and 9a-f were synthesized. The structure of compound 2 was deduced by 1H-NMR, 13C-NMR, FT-IR, MS, microanalysis, and single-crystal X-ray crystallography. The compound crystallized in the monoclinic system, with space group P21/c and cell coordinates a = 8.5752(16) Å, b = 21.046(4) Å, c = 8.2941(12) Å, β = 101.131(6)°, V = 1468.7(4) Å3, and Z = 4. Compounds 2, 3a-c, 4, 5a-c and 9a-f were subjected into in vitro antimicrobial activity tests. Compounds 3a and 3c were more potent than standard drug amphotericin B, showing MIC values of 23.8 ± 0.42 and 24.3 ± 0.68, respectively, against Aspergillus fumigatus while the standard drug MIC was 23.7 ± 0.1. Compound 3c was also more potent (MIC 24.8 ± 0.64) than the standard drug amphotericin B (MIC 19.7 ± 0.2) against Syncephalastrum racemosum. Compounds 4 and 9f also showed promising anti-microbial activity. Molecular modeling was performed for the most active compounds.

Keywords: [2+3] cycloaddition; anti-microbial activity; enaminone; molecular modeling; thiophene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amphotericin B / pharmacology
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / pharmacology*
Antifungal Agents / chemical synthesis
Antifungal Agents / pharmacology*
Aspergillus fumigatus / drug effects*
Carboxylic Acids / chemical synthesis
Carboxylic Acids / pharmacology*
Crystallography, X-Ray
Microbial Sensitivity Tests
Models, Molecular
Mucorales / drug effects*
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / pharmacology*

Substances

Anti-Bacterial Agents
Antifungal Agents
Carboxylic Acids
Thiophenes
ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate
Amphotericin B