Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes

Maghraby, Mohammed T.-E.; Abou-Ghadir, Ola M Fahmy; Abdel-Moty, Samia G.; Ali, Asmaa Y.; Salem, Ola I. A.

doi:10.1016/j.bmc.2020.115403

Cited by 90 publications

(53 citation statements)

References 37 publications

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“…The hydrophobic interactions of imidazole ring, pyrazole, and phenyl substituents with Leu338, Ala513, Leu517, Val509, Tyr341, and Val335 residues lining the COX‐2 hydrophobic pocket facilitated the anti‐inflammatory potential of the test compounds. Similarly, the π – π interactions between imidazole ring of benzimidazole with Gln178 and Ala513, in addition to the hydrogen bonding interactions with Ser339 and Asp501 validated the selective COX‐2 inhibitory profile of the test hybrid compounds (Maghraby, Ghadir, Moty, Ali, & Salem, 2020). The substituted thiazole derivatives 102a–g (Figure 16) promoted the selective COX‐2 inhibition profile of thiazoles compared to benzothiazoles.…”

Section: Selective Cox‐2 Inhibitors Based On Azole Nucleusmentioning

confidence: 73%

“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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Section: Selective Cox‐2 Inhibitors Based On Azole Nucleusmentioning

confidence: 73%

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

Prasher

Sharma

2020

Drug Development Research

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“…Further modifications of MPK334, such as synthetic hybrids with a benzimidazolyl group, could potentially increase its anthelmintic activity [ 34 ]. Conjugation of an additional moiety on YAK308 may increase potency, as has been demonstrated for other anti-parasitic (e.g., aryl-thiazole derivatives) [ 33 ] and anti-inflammatory drugs (e.g., benzimidazole-thiazole hybrids) [ 35 ]. The newly synthesised analogues would need to be re-tested in vitro against larvae and then on H. contortus adults—which are responsible for haemonchosis in ruminant hosts and are the target for treatment in the stomach (i.e., abomasum).…”

Section: Resultsmentioning

confidence: 99%

Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro

et al. 2021

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Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three—designated MPK18, MPK334 and YAK308—induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC50 values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC50 values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure–activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus.

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“…The synthesized hybrids containing the acetyl group 195, phenyl thiosemicarbazone 196 and 1,3-thiazolines 197a-c were demonstrated to be the most selective COX-2 as well as 15-LOX inhibitors, that is, due to the fact they provided a collaboration of not only molecular volume advantages but also steric, electronic, hydrogen bonding and hydrophobic advantages that are essential to confirm the optimal molecular interactions with the specific biological boards and to inhibit their biological responses. Currently, the importance of these derivatives connected to diverse aromatic and heterocyclic rings for evolving innovative anti-inflammatory agents with dual COX-2 /15-LOX enzyme inhibitory efficacy is avowed [74]. Finally, some new 4-(4-chlorophenyl)thiazol-2-amines 200 were prepared via cyclic condensation of an α-bromoketone 199 and N-substituted thiourea 198 in anhydrous ethanol, stirring under microwave irradiation at 80 °C for 30 min.…”

Section: -Aminothiazoles As Anti-inflammatory Agentsmentioning

confidence: 99%

An Overview on Synthetic 2-Aminothiazole-Based Compounds Associated with Four Biological Activities

2021

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Amongst sulfur- and nitrogen-containing heterocyclic compounds, the 2-aminothiazole scaffold is one of the characteristic structures in drug development as this essential revelation has several biological activities abiding it to act as an anticancer, antioxidant, antimicrobial and anti-inflammatory agent, among other things. Additionally, various 2-aminothiazole-based derivatives as medical drugs have been broadly used to remedy different kinds of diseases with high therapeutic influence, which has led to their wide innovations. Owing to their wide scale of biological activities, their structural variations have produced attention amongst medicinal chemists. The present review highlights the recently synthesized 2-aminothiazole-containing compounds in the last thirteen years (2008–2020). The originality of this proposal is based on the synthetic strategies developed to access the novel 2-aminothiazole derivatives (N-substituted, 3-substituted, 4-substituted, multi-substituted, aryl/alkyl substituents or acyl/other substituents). The literature reports many synthetic pathways of these 2-aminothiazoles associated with four different biological activities (anticancer, antioxidant, antimicrobial and anti-inflammatory activities). It is wished that this review will be accommodating for new views in the expedition for rationalistic designs of 2-aminothiazole-based medical synthetic pathways.

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Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes

Cited by 90 publications

References 37 publications

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

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

Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro

An Overview on Synthetic 2-Aminothiazole-Based Compounds Associated with Four Biological Activities

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