Sulfonamide chalcone as a new class of α-glucosidase inhibitors

Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro.

Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5- HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma. In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors.

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Structure and Ligand Based Drug Design Strategies in the Development of Novel 5-LOX Inhibitors

We report the discovery of new, low micromolar, small molecule inhibitors of human platelet-type 12- and reticulocyte 15-lipoxygenase-1 (12-hLO and 15-hLO) using structure-based methods. Specifically, we created homology models of 12-hLO and 15-hLO, based on the structure of rabbit 15-lipoxygenase, for in silico screening of a large compound library followed by in vitro screening of 20 top scoring molecules. Eight of these compounds inhibited either 12- or 15-human lipoxygenase with lower than 100 microM affinity. Of these, we obtained IC50 values for the three best inhibitors, all of which displayed low micromolar inhibition. One compound showed specificity for 15-hLO versus 12-hLO; however, a selective inhibitor for 12-hLO was not identified. As a control we screened 20 randomly selected compounds, of which none showed low micromolar inhibition. The new low-micromolar inhibitors appear to be suitable as leads for further inhibitor development efforts against 12-hLO and 15-hLO, based on the fact their size and chemical properties are appropriate to classify them as drug-like compounds. The models of these protein-inhibitor complexes suggest strategies for future development of selective lipoxygenase inhibitors.

Novel human lipoxygenase inhibitors discovered using virtual screening with homology models.

Introduction: Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family that possess a wide variety of cytoprotective and modulatory functions, which may have therapeutic potential for multiple diseases. Their physicochemical properties seem to define the extent of their biological activity. Areas covered: A comprehensive synopsis of recent patent literature (2005 – 2011) describing chalcones and their derivatives on selected activities (e.g., anti-inflammatory, antimitotic, cytotoxic, antioxidant, anti-infection) is provided in this paper. Synthesis, combinatorial techniques, biological evaluation in vitro/in vivo, and new biological assays are discussed. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. Expert opinion: Several natural and synthetic chalcones and their derivatives appear as promising anti-inflammatory and anticancer activities. Their clinical evaluation will be c...

Recent progress in therapeutic applications of chalcones

Development of 3D-QSAR models for 5-lipoxygenase antagonists: chalcones.

Background: Bergenin, 4-O-methyl gallic acid glucoside, is a bioactive compound found in the cortex of Mallotus japonicus (L.f.) Müll.Arg. along with many other natural resources including that from Bergenia species. The present study delineates the neuroprotective potential of bergenin through the modulation of PPAR-γ receptors. Method: Dementia was induced in the Wistar rats by intraperitoneal (i.p.) administration of sodium azide (12.5 mg/kg for the first 5 days followed by 10 mg/kg for the next 9 days). The rats were then exposed to the Morris water maze test to assess the effect on cognitive abilities followed by a series of biochemical and histopathological evaluations. Results: Sodium azide-treated rats exhibited a severe deterioration of memory as suggested by poor performance in the spatial learning task in addition to the enhancement of brain acetylcholinesterase potential, oxidative stress, inflammation, and amyloid-β (Aβ) accumulation. Administration of bergenin to sodium azide-treated rats significantly recovered cognition and related biochemical variations. Further, co-administration of Bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist with bergenin challenged its neuroprotective effects. Conclusions: The findings of our study exhibit that the cognitive restoration potential of bergenin may be attributed to its modulatory effects against cholinesterase, oxidative stress, and inflammatory markers, as well as its neuroprotective actions, thus aligning it as a possible therapy for Alzheimer’s disease-related dementia. The study also fortifies the significance of PPAR-γ receptors in dementia. Graphical Abstract

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M Arockia Babu

Papers

Development of 3D-QSAR models for 5-lipoxygenase antagonists: chalcones.

Bergenin ameliorates cognitive deficits and neuropathological alterations in sodium azide-induced experimental dementia