Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β -glucuronidase inhibitors

Taha, Muhammad; Baharudin, Mohd Syukri; Ismail, Nor Hadiani; Selvaraj, Manikandan; Salar, Uzma; Al-Kadi, Khaled Abdullah Ali; Khan, Khalid Mohammed

doi:10.1016/j.bioorg.2017.01.015

Cited by 29 publications

(7 citation statements)

References 45 publications

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“…hydroxyl for methoxy and imine for more polar sulfonamide unit ( Fig. 26), led to stronger bGLU inhibitory potency for the resulting oxadiazole-benzenesulfonamides [197]. The most potent inhibitors were compounds 116 and 117 with IC 50 ¼ 2.40 and 6.34 mM respectively; compound 116 showed similar potency as compound 113.…”

Section: 214mentioning

confidence: 97%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

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BiomarkerEnzyme inhibition Molecular target Structure activity relationship a b s t r a c tThe emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, b-glucuronidase (bGLU) e a lysosomal acid hydrolase responsible for the catalytic deconjugation of b-D-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of bGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of bGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved bGLU inhibitory potency and the development of new therapeutic agents in consequential.

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Section: 214mentioning

confidence: 97%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

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“…β-Glucuronidase is an important glycosidase enzyme with great biological importance, which provides space towards the libraries of small organic inhibitors designing [26–27]. It’s over expression is associated with several cancers [28].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics: A rational combine approach used for the identification and in-vitro activity evaluation of potent β-Glucuronidase inhibitors

et al. 2018

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Identification of hotspot drug-receptor interactions through in-silico prediction methods (Pharmacophore mapping, virtual screening, 3DQSAR, etc), is considered as a key approach in drug designing and development process. In the current design study, advanced in-silico based computational techniques were used for the identification of lead-like molecules against the targeted receptor β-glucuronidase. The binding pattern of a potent inhibitor in the ligand-receptor X-ray co-crystallize complex was used to identify and extract the structure-base Pharmacophore features. Based on these observations; five structure-based pharmacophore models were derived to conduct the virtual screening of ICCBS in-house data-base. Top-ranked identified Hits (33 compounds) were selected to subject for in-vitro biological activity evaluation against β-glucuronidase enzyme; out of them, twenty compounds (61% of screened compounds) evaluated as actives, however eleven compounds were found to have significantly higher inhibitory activity, including compounds 1, 5–8, 10, 12–13, and 17–19 with IC50 values ranging from 1.2 μM to 34.9 μM. Out of the eleven potent inhibitors, seven compounds 1, 5, 6, 7, 8, 13, and 19 were found new, and evaluated first time for the β-glucuronidase inhibitory activity. Compounds 1, 5 and 19 exhibited a highly potent inhibition in uM of β-glucuronidase enzyme with non-cytotoxic behavior against the mouse fibroblast (3T3) cell line. Our combined in-silico and in-vitro results revealed that the binding pattern analysis of the eleven potent inhibitors, showed almost similar non-covalent interactions, as observed in case of our validated pharmacophore model. The obtained results thus demonstrated that the virtual screening minimizes false positives, and provide a template for the identification and development of new and more potent β-glucuronidase inhibitors with non-toxic effects.

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“…Compound 322 was identified as a lead compound for bglucuronidase inhibitory activity and may be used for further research for finding a powerful inhibitor [241]. Very recently, Iqbal and coworkers developed a class of chalcone-sulfonamide hybrids as potent alkaline phosphatase inhibitors.…”

Section: Miscellaneousmentioning

confidence: 99%

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

Zhao

Rakesh

Ravidar

et al. 2019

European Journal of Medicinal Chemistry

409

183

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a b s t r a c tSulfur (S VI ) based moieties, especially, the sulfonyl or sulfonamide based analogues have showed a variety of pharmacological properties, and its derivatives propose a high degree of structural diversity that has established useful for the finding of new therapeutic agents. The developments of new less toxic, low cost and highly active sulfonamides containing analogues are hot research topics in medicinal chemistry. Currently, more than 150 FDA approved Sulfur (S VI )-based drugs are available in the market, and they are widely used to treat various types of diseases with therapeutic power. This comprehensive review highlights the recent developments of sulfonyl or sulfonamides based compounds in huge range of therapeutic applications such as antimicrobial, anti-inflammatory, antiviral, anticonvulsant, antitubercular, antidiabetic, antileishmanial, carbonic anhydrase, antimalarial, anticancer and other medicinal agents. We believe that, this review article is useful to inspire new ideas for structural design and developments of less toxic and powerful Sulfur (S VI ) based drugs against the numerous death-causing diseases.

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Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β -glucuronidase inhibitors

Cited by 29 publications

References 45 publications

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Bioinformatics: A rational combine approach used for the identification and in-vitro activity evaluation of potent β-Glucuronidase inhibitors

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

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