Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors

Ragab, F. M.; Heiba, Helmy I.; El‐Gazzar, Marwa G.; Abou‐Seri, Sahar M.; El-Sabbagh, Walaa A.; El‐Hazek, Reham M. M.

doi:10.1039/c6md00367b

Cited by 24 publications

(11 citation statements)

References 30 publications

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“…8). 43 Surprisingly, the quinoline scaffold as a novel COX-2 inhibitor has also been investigated as an anti-breast cancer agent (mediated by COX-2 inhibition). In particular, a new group of 4-(imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl moiety at the para position of the C-2 phenyl ring demonstrated good inhibition with IC 50 values in the potent range of 0.063-0.090 μM (Fig.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

2017

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Most drugs used to treat pain and inflammation act through inhibition of the enzymes prostaglandin G/H synthase, commonly known as cyclooxygenase (COX). Among these, the simultaneous inhibition of cyclooxygenase 1 (COX-1) would explain the unwanted side effects in the gastrointestinal tract and many adverse cardiovascular effects, such as high blood pressure, myocardial infarction and thrombosis. These side effects led in time to the development of NSAIDs that behave as selective COX-2 inhibitors. This manuscript highlights the structure-activity relationships which characterize the chemical scaffolds endowed with selective COX-2 inhibition. Additionally, the role of COX-2 inhibitors in the pain phenomenon and cancer is discussed.

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Section: Introductionmentioning

confidence: 99%

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

2017

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“…The acute toxicity analysis revealed high biological tolerance of these derivatives compared to the standard drug celecoxib. Reportedly, the test compounds displayed similar docking profile as that of celecoxib in the active site of COX‐2 isoenzyme by accommodating deeply into the side pocket of enzyme while interacting Arg513 and His90, critical for COX‐2 selectivity (Ragab et al, 2016). The novel set of compounds 88–89 (Figure 15) containing substituted thiazoles displayed preferential COX‐2 inhibition in vitro.…”

Section: Selective Cox‐2 Inhibitors Based On Azole Nucleusmentioning

confidence: 92%

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

Prasher

Sharma

2020

Drug Development Research

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An over‐expression of COX‐2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro‐inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over‐activity of COX‐2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX‐2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state‐of‐the‐art drug designing strategies. The heterocyclic “azole” scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y‐shaped molecules and the eminence of bulkier group for COX‐2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore‐profile of the chemotherapeutics based on azole motif for a selective targeting of the COX‐2 isoenzyme.

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“…In a previous work, we started to explore the anti‐inflammatory and COX‐2 selectivity of 1,3,4‐thiadiazole scaffold. [ 10,11 ] Different novel derivatives were synthesized, and their established high potency and selectivity encouraged us to design a novel series of thiadiazole‐based compounds with various substituents using the structure–activity relationship (SAR) of potent drugs and reported COX‐2 inhibitors [ 12 ] and maintaining the pharmacophoric requirements for selective binding to COX‐2 enzyme.…”

Section: Introductionmentioning

confidence: 99%

Anti‐inflammatory and analgesic effect of LD‐RT and some novel thiadiazole derivatives through COX‐2 inhibition

El‐Hazek

El-Sabbagh

El-Hazek

et al. 2020

Archiv der Pharmazie

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Generally, highly selective COX-2 inhibitors cause cardiovascular side effects. Celecoxib is the highly marketed coxib, so there is still a need for the synthesis of COX-2 inhibitors with less adverse effects. Moreover, low-dose radiotherapy (LD-RT) is clinically used for the treatment of inflammatory diseases. The present study aimed to investigate the analgesic and anti-inflammatory activity of a novel series of 1,3,4-thiadiazole derivatives alone or combined with LD-RT with a single dose of 0.5 Gy. Initially, in vitro COX-1/COX-2 inhibition assays were performed, identifying the sulfonamide-containing compounds 5-10 as the most potent candidates, with IC 50 values in the range of 0.32-0.37 µM and the highest selectivity indices. These compounds and celecoxib were subjected to in vivo examination after their safety was assessed through the acute toxicity test. Treatment with compounds 5-10 inhibited carrageenan-induced edema by nearly 47-56%, which was nearly equivalent to celecoxib. Compounds 7 and 8 and celecoxib showed an analgesic activity of 64.15%, 49.05%, and 84.90%, respectively, whereas compounds 5, 6, 9, and 10 did not show any analgesic activity unless combined with LD-RT. Ulcerogenic activity, histological paw examination, and docking studies were performed. Compounds 5-10 were nearly similar to celecoxib, showing normal histological features with no ulcerogenic activity.

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Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors

Abstract: A novel series of thiadiazole derivatives were designed and synthesized for evaluation as selective COX-2 inhibitors in vitro and were investigated in vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats.

Cited by 24 publications

References 30 publications

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

Anti‐inflammatory and analgesic effect of LD‐RT and some novel thiadiazole derivatives through COX‐2 inhibition

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