Unveiling a novel pyrazolopyrimidine scaffold as a dual COX-2/5-LOX inhibitor with immunomodulatory potential: Design, synthesis, target prediction, anti-inflammatory activity, and ADME-T with docking simulation

Article

作者: Ammar, Yousry A ; Ayman, Radwa ; Ragab, Ahmed ; Salem, Mohamed A ; Abusaif, Moustafa S

Dual-target COX-2/5-LOX inhibitors are regarded as a rational strategy for the design of potent anti-inflammatory agents with favorable safety profiles. In this study, novel pyrazolo[1,5-a]pyrimidine derivatives were synthesized, developed, and screened for their ability to inhibit the cyclooxygenase-2 enzyme in vitro, with comparisons made to the established inhibitors Celecoxib and Meloxicam. Spectroscopic analyses confirmed the structure of the designed derivatives. The target prediction using AI was performed to identify potential targets that could be engaged through Swiss target prediction database. The SAR study was established by incorporating various substituents and nuclei into the pyrazolopyrimidine pharmacophore. The synthesized pyrazolopyrimidines exhibited IC₅₀ values ranging from 53.32 ± 4.43 to 254.90 ± 6.45 nM, in comparison to Celecoxib (IC₅₀ = 6.73 ± 5.69 nM) and Meloxicam (IC₅₀ = 52.35 ± 6.66 nM). Notably, compound 5a was identified as the most active derivative, demonstrating an IC₅₀ of 53.32 ± 4.43 nM. The three most prominent pyrazolopyrimidine derivatives, 3a, 5a, and 6a, were subsequently evaluated for their ability to inhibit the COX-1 and 5-LOX enzymes. Compounds 3a, 5a, and 6a demonstrated inhibitory activity against COX-1, with IC₅₀ values of 476.45 ± 16.56, 757.51 ± 2.61, and 169.13 ± 5.77 nM, respectively. These derivatives 3a, 5a, and 6a showed significant selectivity index values of 7.91, 14.20, and 2.80, respectively, toward COX-2 rather than COX-1 in comparison to Meloxicam (SI = 0.75) and Celecoxib (SI = 2.35). Moreover, compound 5a exhibited 86 % inhibition compared to Zileuton's 88 %, while compounds 3a and 6a displayed inhibition rates of 84 % and 80 %, respectively, at a concentration of 100 μM. The most potent compound 5a, demonstrated the highest 5-LOX inhibitory activity, with IC₅₀ of 2.292 ± 0.14 μM. The most promising pyrazolopyrimidine derivative 5a demonstrated a down-regulation of TNF-α and IL-6 gene expression by approximately 0.3826-fold and 0.2732-fold, respectively, when compared to Celecoxib, which induced reductions of 0.2320-fold and 0.2730-fold in these cytokines to promote apoptosis in RAW264.7 cells. Finally, in-silico ADME-T and docking simulations were conducted to predict the oral bioavailability, toxicity, and binding interactions with binding affinity.

2024-12-31·Journal of Enzyme Inhibition and Medicinal Chemistry

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof

Article

作者: Al-Kubeisi, Ahmed K. ; Hazzaa, Aly A. ; El-Zemity, Saad R. ; Nassra, Rasha A. ; El-Miligy, Mostafa M. M.

New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC₅₀= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC₅₀= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

2024-09-01·Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Novel Dual COX-2/5-LOX Inhibitory Activity by Chalcone Derivatives: A Safe and Efficacious Anti-inflammatory Agent

Article

作者: Kushwah, Ajay Singh ; Sharma, Shailesh ; Mittal, Amit ; Mittal, Roopal

Background:Non-communicable diseases are chronic systemic inflammation in humans that occurs because of enhanced inflammatory mediators of the arachidonic acid cas-cade. We aimed to explore whether the lead chalcone compounds could exhibit anti-inflam-matory activity via dual blockage of COX-2/5-LOX enzymes and their regulatory mechanism.Methods:RAW 264.7 macrophages were collected from NCC, Pune, for in-vitro experiments. The IC50 values of chalcone compounds C45 and C64 were calculated. RAW 264.7 macro-phages were treated with C45 and C64 (10%, 5%, 2.5%, 0.125%, and 0.0625% concentration). The cell viability was carried out with an MTT assay. The COX-1, COX-2, 5-LOX, PGE2, and LTB4 levels were detected by ELISA-based kits. The in-vivo evaluation was carried out in Male Wistar rats (250-300 g, 7-8 weeks old) with acute and chronic anti-inflammatory models and histopathological studies on the stomach, liver, and kidney.Results:The present study described the in-vitro and in-vivo biological evaluation of dual COX-2/5-LOX inhibitors in chalcone derivatives (C45 and C64) compounds showed the most effective COX-2 and 5-LOX inhibition with IC50 values 0.092 and 0.136μM respectively. Simultaneously, compound C64 showed comparable selectivity towards COX-2 with a Selec-tivity Index (SI) of 68.43 compared to etoricoxib, with an SI of 89.32. In-vivo carrageenan-induced rat paw oedema activity, the compound C64 showed a significant reduction in oedema with 78.28% compared to indomethacin with 88.07% inhibition. Furthermore, cotton pellet-induced granuloma activity revealed that compound C64 significantly reduced 32.85% com-pared with standard 40.13% granuloma inhibition.Conclusion:The chalcone compound C64, (E)-1-(4-Amino-2-hydroxyphenyl)-3-(3,4,5-tri-methoxyphenyl)-prop-2-en-1-one was proved to be a potent and novel Dual COX-2/5-LOX inhibitor with improved gastric safety profiling.

100 项与 COX-2/5-LOX inhibitors(University of Alberta) 相关的药物交易

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