Development of pyrazole and pyrazolopyrimidine derivatives as promising anti-MRSA agents targeting penicillin-binding protein (PBP2a) and mecA gene.
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| Názov: | Development of pyrazole and pyrazolopyrimidine derivatives as promising anti-MRSA agents targeting penicillin-binding protein (PBP2a) and mecA gene. |
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| Autori: | Ragab A; Chemistry Department, Faculty of Science (Boys), Al-Azhar University, 11884 Nasr City, Cairo, Egypt; Chemistry Department, Faculty of Science, Galala University, Galala City 43511, Suez, Egypt., Abusaif MS; Chemistry Department, Faculty of Science (Boys), Al-Azhar University, 11884 Nasr City, Cairo, Egypt; Department for Synthesis and Characterization of Polymers, Polymer Institute of the Slovak Academy of Sciences SAS, Dúbravská cesta 9, 845 41 Bratislava, Slovak Republic., Selim HMRM; Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia., Riad OKM; Microbiology and Immunology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 35527, Egypt., Helal MH; Center for Scientific Research and Entrepreneurship, Northern Border University, Arar 73213, Saudi Arabia. Electronic address: mohammed.hlal7@yahoo.com., Ali AM; Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo 11754, Egypt., Ammar YA; Chemistry Department, Faculty of Science (Boys), Al-Azhar University, 11884 Nasr City, Cairo, Egypt., Ahmed GE; Canal higher Institute for Engineering and Technology, Suez, Egypt. |
| Zdroj: | Bioorganic chemistry [Bioorg Chem] 2025 Oct; Vol. 165, pp. 108977. Date of Electronic Publication: 2025 Sep 09. |
| Spôsob vydávania: | Journal Article |
| Jazyk: | English |
| Informácie o časopise: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| Výrazy zo slovníka MeSH: | Pyrazoles*/pharmacology , Pyrazoles*/chemistry , Pyrazoles*/chemical synthesis , Methicillin-Resistant Staphylococcus aureus*/drug effects , Methicillin-Resistant Staphylococcus aureus*/genetics , Anti-Bacterial Agents*/pharmacology , Anti-Bacterial Agents*/chemistry , Anti-Bacterial Agents*/chemical synthesis , Penicillin-Binding Proteins*/genetics , Penicillin-Binding Proteins*/antagonists & inhibitors , Penicillin-Binding Proteins*/metabolism , Bacterial Proteins*/genetics , Bacterial Proteins*/antagonists & inhibitors , Bacterial Proteins*/metabolism , Pyrimidines*/pharmacology , Pyrimidines*/chemistry , Pyrimidines*/chemical synthesis, Microbial Sensitivity Tests ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Biofilms/drug effects ; Antifungal Agents/pharmacology ; Antifungal Agents/chemical synthesis ; Antifungal Agents/chemistry |
| Abstrakt: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Global health is threatened by methicillin-resistant S. aureus (MRSA). The rising prevalence of MRSA complicates anti-infective treatment strategies, highlighting the urgent need for novel therapeutics targeting MRSA. In this study, novel pyrazole and pyrazolopyrimidine derivatives were synthesized and comprehensively characterized using IR, 1 H/ 13 C NMR, and elemental analysis. Significant anti-microbial activity of these derivatives was demonstrated (using MIC test) against both Gram-positive (S. aureus ATCC 25923 and MRSA ATCC 43300) and Gram-negative bacteria (E. coli ATCC 25922 and K. pneumoniae ATCC 700603), in addition to exhibiting antifungal activity against C. albicans ATCC 10231. Notably, the Schiff bases pyrazoles 6b and 6c represent the most promising derivatives in comparison to the positive control drugs (neomycin sulfate and fluconazole). Additionally, MBC/MFC tests exhibited bactericidal and fungicidal activity, except for pyrazole derivative 3a, which demonstrated bacteriostatic efficacy specifically against MRSA. The promising compounds 6b and 6c showed strong antibiofilm activity against MRSA, resulting in a reduction of biofilm formation by 74.1 % and 71.36 %, respectively, at ½ MIC. Schiff base pyrazoles (6b and 6c) showed specific activity against MRSA, by revealing a reduction in expression of PBP2a protein levels using Western blotting. Additionally, polymerase chain reaction and sequencing of the mecA gene confirmed induced mutations following exposure to these compounds, suggesting a dual mechanism of action at both phenotypic and genotypic levels. Finally, the in-silico ADME studies for the promising derivatives were successful in predicting their oral bioavailability, drug-likeness, and pharmacokinetic features. (Copyright © 2025 Elsevier Inc. All rights reserved.) |
| Contributed Indexing: | Keywords: ADME prediction; Penicillin binding protein 2A; Pyrazoles and pyrazolo[1,5-a]pyrimidine; mecA gene |
| Substance Nomenclature: | 0 (Pyrazoles) 0 (Anti-Bacterial Agents) 0 (Penicillin-Binding Proteins) 0 (Bacterial Proteins) 0 (Pyrimidines) 0 (mecA protein, Staphylococcus aureus) 3QD5KJZ7ZJ (pyrazole) 0 (Antifungal Agents) |
| Entry Date(s): | Date Created: 20250914 Date Completed: 20251021 Latest Revision: 20251120 |
| Update Code: | 20251121 |
| DOI: | 10.1016/j.bioorg.2025.108977 |
| PMID: | 40946518 |
| Databáza: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />Global health is threatened by methicillin-resistant S. aureus (MRSA). The rising prevalence of MRSA complicates anti-infective treatment strategies, highlighting the urgent need for novel therapeutics targeting MRSA. In this study, novel pyrazole and pyrazolopyrimidine derivatives were synthesized and comprehensively characterized using IR, <sup>1</sup> H/ <sup>13</sup> C NMR, and elemental analysis. Significant anti-microbial activity of these derivatives was demonstrated (using MIC test) against both Gram-positive (S. aureus ATCC 25923 and MRSA ATCC 43300) and Gram-negative bacteria (E. coli ATCC 25922 and K. pneumoniae ATCC 700603), in addition to exhibiting antifungal activity against C. albicans ATCC 10231. Notably, the Schiff bases pyrazoles 6b and 6c represent the most promising derivatives in comparison to the positive control drugs (neomycin sulfate and fluconazole). Additionally, MBC/MFC tests exhibited bactericidal and fungicidal activity, except for pyrazole derivative 3a, which demonstrated bacteriostatic efficacy specifically against MRSA. The promising compounds 6b and 6c showed strong antibiofilm activity against MRSA, resulting in a reduction of biofilm formation by 74.1 % and 71.36 %, respectively, at ½ MIC. Schiff base pyrazoles (6b and 6c) showed specific activity against MRSA, by revealing a reduction in expression of PBP2a protein levels using Western blotting. Additionally, polymerase chain reaction and sequencing of the mecA gene confirmed induced mutations following exposure to these compounds, suggesting a dual mechanism of action at both phenotypic and genotypic levels. Finally, the in-silico ADME studies for the promising derivatives were successful in predicting their oral bioavailability, drug-likeness, and pharmacokinetic features.<br /> (Copyright © 2025 Elsevier Inc. All rights reserved.) |
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| ISSN: | 1090-2120 |
| DOI: | 10.1016/j.bioorg.2025.108977 |