The development of thymol-isatin hybrids as broad-spectrum antibacterial agents with potent anti-MRSA activity.

Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound AS8 was the most effective against methicillin-resistant Staphylococcus aureus (MIC = 1.9 µM and MBC = 3.9 µM), exhibiting biofilm inhibitory potential. AS8 exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover, AS8 was found to be non-toxic and showed a potent in vivo antibacterial efficacy (90% survival at 10 mg kg-1) as well as a modulated immune response in the larva-based (Galleria mellonella) model of systemic infections. Overall findings confirmed that AS8 can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.

Past, present and future of xanthine oxidase inhibitors: design strategies, structural and pharmacological insights, patents and clinical trials.

Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism. Xanthine oxidase is more involved in pathological conditions when extensively modulated. Elevation of xanthine oxidase is not only the prime cause of gout but is also responsible for various hyperuricemia associated pathological conditions like diabetes, chronic wounds, cardiovascular disorders, Alzheimer's disease, etc. Currently available xanthine oxidase inhibitors in clinical practice (allopurinol, febuxostat and topiroxostat) suffer from fatal side effects that pose a serious problem to the healthcare system, raising global emergency to develop novel, potent and safer xanthine oxidase inhibitors. This review will provide key and systematic information about: a. design strategies (inspired from both marketed drugs in clinical practice and natural products), structural insights and pharmacological output (xanthine oxidase inhibition and associated activities) of various pre-clinical candidates reported by various research groups across the globe in the past two decades; b. patented xanthine oxidase inhibitors published in the last three decades and c. clinical trials and their outcomes on approved drug candidates. Information generated in this review has suggested fragment-based drug design (FBDD) and molecular hybridization techniques to be most suitable for development of desired xanthine oxidase inhibitors as one provides high selectivity toward the enzyme and the other imparts multifunctional properties to the structure and both may possess capabilities to surpass the limitations of currently available clinical drugs. All in combination will exclusively update researchers working on xanthine oxidase inhibitors and allied areas and potentially help in designing rational, novel, potent and safer xanthine oxidase inhibitors that can effectively tackle xanthine oxidase related disease conditions and disorders.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Protective effect of Grewia asiatica leaves extract in animal models of epilepsy and anxiety.

Grewia asiatica Linn. is a well-known plant for its nutritional and therapeutic attributes. It has been mentioned in ancient Indian literature as Rasayana due to its stimulant and tonic effects. Thus, present investigation was carried out to evaluate the antiepileptic and anxiolytic action of G. asiatica Linn. leaves using animal models. Methanol extract at dose levels of 100 and 200 mg/kg was capable of providing protection against both pentylenetetrazole and maximal electroshock induced seizures in mice. Extract also showed significant anxiolytic activity in elevated plus maze, light/dark box and mirror chamber mice models at same dose levels. Results of this study indicated that the methanol extract of leaves of G. asiatica plant possess significant antiepileptic and anxiolytic effect.

Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity.

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 µM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 µM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.

Design, Synthesis, Antimicrobial Evaluation, and Molecular Modeling Studies of Novel Indolinedione-Coumarin Molecular Hybrids.

Keeping in view various pharmacological attributes of indole and coumarin derivatives, a new series of indolindione-coumarin molecular hybrids was rationally designed and synthesized. All synthesized hybrid molecules were evaluated for their antimicrobial potential against Gram-negative bacterial strains (Escherichia coli and Salmonella enterica), Gram-positive bacterial strains (Staphylococcus aureus and Mycobacterium smegmatis), and four fungal strains (Candida albicans, Alternaria mali, Penicillium sp., and Fusarium oxysporum) by using the agar gel diffusion method. Among all synthetics, compounds K-1 and K-2 were found to be the best antimicrobial agents with the minimum inhibitory concentration values of 30 and 312 µg/mL, against Penicillium sp. and S. aureus, respectively. The biological data revealed some interesting facts about the structure-activity relationship which state that the electronic environment on the indolinedione moiety and carbon chain length between indolinedione and triazole moieties considerably affect the antimicrobial potential of the synthesized hybrids. Various types of binding interactions of K-2 within the active site of S. aureus dihydrofolate reductase were also streamlined by molecular modeling studies, which revealed the possible mechanism for potent antibacterial activity of the compound.

Estrogen attenuates renal IRI through PPAR-γ agonism in rats.

BACKGROUND: Estrogen is reported to be renoprotective agent in various preclinical studies, attributing to its antioxidant and anti-inflammatory potential. The aim of present study was to investigate the involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) in estrogen-mediated protection against renal ischemia reperfusion injury (IRI) in rats. MATERIALS AND METHODS: The renal damage induced by IRI (40-min ischemia and 24-h reperfusion) was assessed by measuring serum creatinine, creatinine clearance, blood urea nitrogen, serum uric acid, electrolytes, and microproteinuria in rats. The myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. Hematoxylin-eosin and periodic acid schiff staining of renal tissues were done to demonstrate histopathologic changes. Estrogen (0.2, 0.5, and 1.0 mg/kg, i.p.) was administered 1 h before subjecting rats to renal IRI. Separately, bisphenol A diglycyl ether (BADGE, 30 mg/kg, i.p.), a PPAR-γ receptor antagonist, was given before estrogen administration followed by IRI in rats. RESULTS: The ischemia reperfusion demonstrated renal damage in rats with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. Estrogen administration demonstrated marked renoprotection that was attenuated by BADGE pretreatment in rats. CONCLUSIONS: It is concluded that PPAR-γ agonism serves as one of the mechanisms in estrogen-mediated renoprotection.

Design and synthesis of aza-flavones as a new class of xanthine oxidase inhibitors.

In an attempt to develop non-purine-based xanthine oxidase (XO) inhibitors, keeping in view the complications reported with the use of purine-based XO inhibitors, the flavone framework (a class possessing XO inhibitory potential) was used as lead structure for further optimization. By means of structure-based classical bioisosterism, quinolone was used as an isoster for chromone (a bicyclic unit present in flavones), owing to the bioactive potential and drug-like properties of quinolones. This type of replacement does not alter the shape and structural features required for XO inhibition, and also provides some additional interaction sites, without the loss of hydrogen bonding and hydrophobic and arene-arene interactions. In the present study, a series of 2-aryl/heteroaryl-4-quinolones (aza analogs of flavones) was rationally designed, synthesized and evaluated for in vitro XO inhibitory activity. Some notions about structure-activity relationships are presented indicating the influence of the nature of the 2-aryl ring on the inhibitory activity. Important interactions of the most active compound 3l (IC(50) = 6.24 µM) with the amino acid residues of the active site of XO were figured out by molecular modeling.

Ameliorative role of rosiglitazone in hyperhomocysteinemia-induced experimental cardiac hypertrophy.

The present study has been designed to explore the beneficial effect of rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist, in hyperhomocysteinemia-induced cardiac hypertrophy in rats. The hyperhomocysteinemia was induced in rats by feeding L-methionine (1.7 g/kg per day orally) for 8 weeks. The development of cardiac hypertrophy was assessed by measuring ratio of left ventricular weight to body weight, left ventricular wall thickness, cardiomyocyte diameter, and mean arterial blood pressure. The extent of fibrosis was checked by biochemical and histological assessment of collagen deposition. Moreover, the oxidative stress in heart was measured in terms of an increase in thiobarbituric acid reactive substances, superoxide anion generation, and decrease in reduced glutathione levels. The treatment with rosiglitazone (5 and 10 mg/kg per day orally) started from the first day of administration of L-methionine significantly abolished hyperhomocysteinemia-induced increase in left ventricular weight to body weight ratio, left ventricular wall thickness, cardiomyocyte diameter, collagen deposition, and oxidative stress without affecting serum homocysteine levels in rats. At high dose, rosiglitazone markedly reduced mean arterial blood pressure but at low dose, a significant reduction in mean arterial blood pressure was not observed in hyperhomocysteinemic rats. Hence, our results suggest that rosiglitazone provides benefit in hyperhomocysteinemia-induced cardiac hypertrophy and fibrosis in a dose-dependent manner and its protective action is independent of change in mean arterial blood pressure and serum homocysteine levels in rats.