Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

Assali, Mohyeddin; Abualhasan, Murad; Sawaftah, Hadeel; Hawash, Mohammed; Mousa, Ahmed

doi:10.1155/2020/6393428

Cited by 28 publications

(25 citation statements)

References 40 publications

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“…Their blockage of prostaglandin synthesis by inhibiting cyclooxygenase (COX) is responsible for both the desired anti-inflammatory effects and the undesired gastrointestinal effects [ 2 – 4 ]. Based on COX selectivity, NSAIDs are divided into two families: nonselective NSAIDs that block both cyclooxygenase I & II and selective cyclooxygenase II inhibitors [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine

Assali

Abualhasan

Zohud

et al. 2020

International Journal of Analytical Chemistry

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Background. Indomethacin is considered a potent nonsteroidal anti-inflammatory drug that could be combined with Paracetamol to have superior and synergist activity to manage pain and inflammation. To reduce the gastric side effect, they could be combined with Famotidine. Methodology. A codrug of Indomethacin and Paracetamol was synthesized and combined in solution with Famotidine. The quantification of the pharmaceutically active ingredients is pivotal in the development of pharmaceutical formulations. Therefore, a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated according to the International Council for Harmonization (ICH) Q2R1 guidelines. A reverse phase C18 column with a mobile phase acetonitrile: sodium acetate buffer 60 : 40 at a flow rate of 1.4 mL/min and pH 5 was utilized. Results. The developed method showed good separation of the four tested drugs with a linear range of 0.01–0.1 mg/mL (R2 > 0.99). The LODs for FAM, PAR, IND, and codrug were 3.076 × 10−9, 3.868 × 10−10, 1.066 × 10−9, and 4.402 × 10−9 mg/mL respectively. While the LOQs were 9.322 × 10−9, 1.172 × 10−10, 3.232 × 10−9, and 1.334 × 10−8 mg/mL, respectively. Furthermore, the method was precise, accurate, selective, and robust with values of relative standard deviation (RSD) less than 2%. Moreover, the developed method was applied to study the in vitro hydrolysis and conversion of codrug into Indomethacin and Paracetamol. Conclusion. The codrug of Indomethacin and Paracetamol was successfully synthesized for the first time. Moreover, the developed analytical method, to our knowledge, is the first of its kind to simultaneously quantify four solutions containing the following active ingredients of codrug, Indomethacin, Paracetamol, and Famotidine mixture with added pharmaceutical inactive ingredients in one HPLC run.

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Section: Introductionmentioning

confidence: 99%

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine

Assali

Abualhasan

Zohud

et al. 2020

International Journal of Analytical Chemistry

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“…Derivatives of thiazole, 1,2,4-triazole and adamantane, according to the literature, have broad spectrum of biological activities, among which is inhibition of COX-1/COX-2 enzymes [ 56 , 57 , 58 ]. Taking this into account and in order to determine the effect of these compounds on the main pathways controlled by traditional NSAIDS evaluation of inhibitory activity on COX isoforms was performed.…”

Section: Resultsmentioning

confidence: 99%

New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents

et al. 2021

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Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

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“…However, the inhibitory activity against COX1 for most of our synthesized compounds were very close to or better than their tested compound [ 36 ]. In another study by Assali et al, a series of pyrazole and triazole derivatives were synthesized, and one of their triazole derivatives was considered to be a highly selective COX2 inhibitor with a high selectivity ratio (162.5) [ 16 ]. Comparing our results with other studies, the results of this study clearly demonstrate that the synthesized agents have good inhibition activity against both COX1 and COX2 enzymes with relatively low IC 50 values, and the COX selectivity ratio of the compounds synthesized in this study were better than approved drugs like ketoprofen or aspirin.…”

Section: Resultsmentioning

confidence: 99%

“…A standard curve of eight concentrations of prostaglandin, a non-specific binding sample, and a maximum binding sample was used, as instructed in the kit manual, to determine the inhibition of sample compound by applying the multiple regression generated best-fit line. The percentage inhibition of the three concentrations was used to calculate the IC 50 [16].…”

Section: Biological Cox Assay Methodsmentioning

confidence: 99%

“…A lot of classical non-selective NSAIDs were synthesized, approved, and used broadly, such as Ibuprofen, Naproxen, and Ketoprofen (Fig. 1 ), but their selectivity is too low against COX2/COX1 [ 15 ], and the previous studies were implemented to synthesize more selective agents as COX2 inhibitors by using different methods and structures [ 16 ].

Fig.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents

et al. 2020

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Non-steroidal anti-inflammatory drugs are among the most used drugs. They are competitive inhibitors of cyclooxygenase (COX). Twelve novel compounds (aryl acetate and aryl acetic acid groups) were synthesized in this work in order to identify which one was the most potent and which group was most selective towards COX1 and COX2 by using an in vitro COX inhibition assay kit. The cytotoxicity was evaluated for these compounds utilizing MTS assay against cervical carcinoma cells line (HeLa). The synthesized compounds were identified using FTIR, HRMS, 1H-NMR, and 13C-NMR techniques. The results showed that the most potent compound against the COX1 enzyme was 4f with IC50 = 0.725 µM. The compound 3b showed potent activity against both COX1 and COX2 with IC50 = 1.12 and 1.3 µM, respectively, and its selectivity ratio (0.862) was found to be better than Ketoprofen (0.196). In contrast, compound 4d was the most selective with a COX1/COX2 ratio value of 1.809 in comparison with the Ketoprofen ratio. All compounds showed cytotoxic activity against the HeLa Cervical cancer cell line at a higher concentration ranges (0.219–1.94 mM), and the most cytotoxic compound was 3e with a CC50 value of 219 µM. This was tenfold more than its IC50 values of 2.36 and 2.73 µM against COX1 and COX2, respectively. In general, the synthesized library has moderate activity against both enzymes (i.e., COX1 and COX2) and ortho halogenated compounds were more potent than the meta ones.

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Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

Cited by 28 publications

References 40 publications

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine

New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents

Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents

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