Acetylsalicylic acid-sulfa drugs conjugates as potential urease inhibitors and anti-inflammatory agents: bio-oriented drug synthesis, molecular docking, and dynamics simulation studies
To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in differ...
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Published in | Journal of biomolecular structure & dynamics Vol. 42; no. 18; pp. 9373 - 9387 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Taylor & Francis
11.12.2024
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Subjects | |
Online Access | Get full text |
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Summary: | To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR,
1
HNMR,
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CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC
50
of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.
Communicated by Ramaswamy H. Sarma |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0739-1102 1538-0254 1538-0254 |
DOI: | 10.1080/07391102.2023.2252083 |