Innovative design and development of novel thiazole-paracetamol hybrids as COX inhibitors and immunomodulatory activity: design, synthesis, SAR, in vitro biological evaluation, and molecular docking analysis.
6 affiliations
- 1Health Specialties, Basic Sciences and Their Applications Unit, Applied College, Muhayl Asir, King Khalid University Abha 62529 Saudi Arabia.
- 2Department of Chemistry, Faculty of Science (Girls), Al-Azhar University Nasr City Cairo Egypt.
- 3Department of Chemistry, Faculty of Science (boys), Al-Azhar University 11884 Nasr City Cairo Egypt [email protected] [email protected].
- 4Polymer Institute, Slovak Academy of Sciences SAS Dúbravská cesta 9 845 41 Bratislava Slovakia.
- 5Center for Scientific Research and Entrepreneurship, Northern Border University Arar 73213 Saudi Arabia [email protected].
- 6Chemistry Department, Faculty of Science, Galala University Galala City Suez 43511 Egypt [email protected].
Abstract
The hybridization approach was employed to design a single pharmacophore based on the conjugation of paracetamol with thiazole derivatives, yielding thiazole-paracetamol hybrid derivatives 4-11 that utilize a linker from hydrazone (-C[double bond, length as m-dash]N-NH) and azo (-N[double bond, length as m-dash]N-) linkers, serving as the hydrogen bond donor/acceptor binding site. The structure of the designed derivatives was fully characterized and confirmed using analytical data (IR, ¹H NMR, and ¹³C NMR), and elemental analysis. The anti-inflammatory potential of the synthesized hybrids was evaluated using in vitro COX-2 enzymatic inhibition assay. The compounds exhibited moderate to excellent COX-2 inhibitory activity, with IC₅₀ values ranging from 0.81 to 7.27 µM, compared with celecoxib (IC₅₀ = 0.62 ± 0.02 µM). Among the synthesized derivatives, the 5-acetyl-4-methylthiazole candidate 8 emerged as the most potent inhibitor, displaying an IC₅₀ value of 0.81 ± 0.02 µM, whereas the 5-ethoxycarbonyl-4-methylthiazole derivative 7 also demonstrated pronounced activity (IC₅₀ = 1.35 ± 0.15 µM). The SAR analysis revealed that the 4-methylthiazole scaffold was more favorable for COX-2 inhibition than the corresponding 4-oxo-4,5-dihydrothiazole scaffold, while the introduction of compact carbonyl-containing substituents at the C-5 position markedly enhanced inhibitory potency. In contrast, aromatic substitution or incorporation of a 4-oxo-4,5-dihydrothiazole ring reduced activity. Furthermore, compounds 7 and 8 exhibited low-micromolar COX-1 inhibitory activity (IC₅₀ = 0.89 ± 0.05 and 0.72 ± 0.02 µM, respectively), demonstrating dual activity toward COX-1/2 inhibition. In addition, compound 8 effectively suppressed the production of TNF-α and IL-6, with IC₅₀ values of 1.48 ± 0.50 and 1.80 ± 0.35 µM, respectively, showing inhibitory activity comparable to that of celecoxib (IC₅₀ = 1.40 ± 0.10 and 1.74 ± 0.20 µM, respectively). The docking process of the most promising derivative 8 demonstrated strong binding affinity and various types of interactions, including hydrogen bonding, π-π stacking, and hydrophobic interactions (π-alkyl and alkyl). In addition, ADMET prediction indicated a favorable pharmacokinetic profile and acceptable toxicity levels. These findings identify compound 8 as a promising lead candidate for the development of next-generation anti-inflammatory agents with dual cyclooxygenase inhibitory and immunomodulatory properties.
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BibTeX
@article{salem2026innovative,
title = {{Innovative design and development of novel thiazole-paracetamol hybrids as COX inhibitors and immunomodulatory activity: design, synthesis, SAR, in vitro biological evaluation, and molecular docking analysis.}},
author = {Mohamed A Salem and Radwa Ayman and Yousry A Ammar and Moustafa S Abusaif and Mohamed H Helal and Ahmed Ragab},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07351d},
url = {https://europepmc.org/article/MED/42921339},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Innovative design and development of novel thiazole-paracetamol hybrids as COX inhibitors and immunomodulatory activity: design, synthesis, SAR, in vitro biological evaluation, and molecular docking analysis.
AU - Mohamed A Salem
AU - Radwa Ayman
AU - Yousry A Ammar
AU - Moustafa S Abusaif
AU - Mohamed H Helal
AU - Ahmed Ragab
PY - 2026
DA - 2026/10/23
JO - RSC advances
DO - 10.1039/d6ra07351d
UR - https://europepmc.org/article/MED/42921339
AB - The hybridization approach was employed to design a single pharmacophore based on the conjugation of paracetamol with thiazole derivatives, yielding thiazole-paracetamol hybrid derivatives 4-11 that utilize a linker from hydrazone (-C[double bond, length as m-dash]N-NH) and azo (-N[double bond, length as m-dash]N-) linkers, serving as the hydrogen bond donor/acceptor binding site. The structure of the designed derivatives was fully characterized and confirmed using analytical data (IR, ¹H NMR, and ¹³C NMR), and elemental analysis. The anti-inflammatory potential of the synthesized hybrids was evaluated using in vitro COX-2 enzymatic inhibition assay. The compounds exhibited moderate to excellent COX-2 inhibitory activity, with IC₅₀ values ranging from 0.81 to 7.27 µM, compared with celecoxib (IC₅₀ = 0.62 ± 0.02 µM). Among the synthesized derivatives, the 5-acetyl-4-methylthiazole candidate 8 emerged as the most potent inhibitor, displaying an IC₅₀ value of 0.81 ± 0.02 µM, whereas the 5-ethoxycarbonyl-4-methylthiazole derivative 7 also demonstrated pronounced activity (IC₅₀ = 1.35 ± 0.15 µM). The SAR analysis revealed that the 4-methylthiazole scaffold was more favorable for COX-2 inhibition than the corresponding 4-oxo-4,5-dihydrothiazole scaffold, while the introduction of compact carbonyl-containing substituents at the C-5 position markedly enhanced inhibitory potency. In contrast, aromatic substitution or incorporation of a 4-oxo-4,5-dihydrothiazole ring reduced activity. Furthermore, compounds 7 and 8 exhibited low-micromolar COX-1 inhibitory activity (IC₅₀ = 0.89 ± 0.05 and 0.72 ± 0.02 µM, respectively), demonstrating dual activity toward COX-1/2 inhibition. In addition, compound 8 effectively suppressed the production of TNF-α and IL-6, with IC₅₀ values of 1.48 ± 0.50 and 1.80 ± 0.35 µM, respectively, showing inhibitory activity comparable to that of celecoxib (IC₅₀ = 1.40 ± 0.10 and 1.74 ± 0.20 µM, respectively). The docking process of the most promising derivative 8 demonstrated strong binding affinity and various types of interactions, including hydrogen bonding, π-π stacking, and hydrophobic interactions (π-alkyl and alkyl). In addition, ADMET prediction indicated a favorable pharmacokinetic profile and acceptable toxicity levels. These findings identify compound 8 as a promising lead candidate for the development of next-generation anti-inflammatory agents with dual cyclooxygenase inhibitory and immunomodulatory properties.
SN - 2046-2069
ER -