Steroidal 5α-Reductase: A Therapeutic Target for Prostate Disorders

Steroidal 5α-reductase is a system of NADPH dependent enzyme that catalyzes the irreversible conversion of Δ4–3-ketosteroid precursor (testosterone) to its corresponding 5α-reduced metabolite (dihydrotestosterone). Initial role of DHT was discovered through males pseudohermaphroditism, a genetic disorder with complete or partial 5α-reductase deficiency accompanied with features at critical juncture of fetal and postnatal development. However, excessive DHT production, has brought a revolution in revealing the etiology of complications like prostate cancer and benign prostatic hyperplasia. Over the last two decades, converging lines of evidences have highlighted the role of 5α-reductase inhibitors in the treatment of these androgen dependent disorders. Finasteride and Dutasteride, are the two clinically approved inhibitors available in the market, that helps in reducing the prostate volume by blocking the 5a-reductase enzyme

DESIGN, SYNTHESIS, MOLECULAR DOCKING, AND EVALUATION OF CHROMONE BASED TETRAZOLE DERIVATIVES

Objectives: The objective of this research work was to design, synthesize, study the molecular docking, and evaluate the antimicrobial activity of some novel substituted 2-(Phenylamino)-3-(1H-tetrazol-5-yl)-4H-chromen-4-one derivatives (12a-h). Methods: In the present work, 3-Formylchromones were transformed into pharmacologically active substituted 2-(Phenylamino)-3-(1H-tetrazol-5- yl)-4H-chromen-4-one derivatives (12a-h) through a multistep reaction. Initially, synthesis of the substituted 4-Oxo-2-(phenylamino)-4H-chromone-3- carbaldehydes (9a-h) was carried out using substituted acetophenones (6a-h) as starting material and by employing an earlier reported method (1,3-dipolar cycloaddition reaction). Then, these synthesized compounds were converted into respective oximes (10a-h).The obtained oximes (10a-h) were further converted into nitriles (11a-h) which were finally subjected to concerted cycloaddition through stepwise addition of neutral or anionic azide species to furnish final substituted 2-(Phenylamino)-3-(1H-tetrazol-5-yl)-4H-chromen-4-one derivatives (12a-h). All the newly synthesized compounds (12a-h) and a reference compound (ciprofloxacin) were docked into the active site of TyrRS (PDB: 1JIK) by means of the BioPredicta module of VLife MDS. The synthesized compounds (12a-h) were also evaluated in vitro for their antibacterial (against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli bacterial stains) and antifungal activities (against Aspergillus niger and Candida albicans fungal strains) using Zone of Inhibition method. Results: The formation of substituted 2-(Phenylamino)-3-(1H-tetrazol-5-yl)-4H-chromen-4-one derivatives (12a-h) was confirmed through their spectral analysis, that is, 1H-NMR, 13C-NMR, and Mass spectroscopy. During docking study, the recorded molecular binding interactions revealed that all the newly synthesized compounds (12a-h) interacted well with binding site of the enzyme. The synthesized compounds were also evaluated in vitro for their antibacterial (against S. aureus, B. subtilis, P. aeruginosa, and E. coli bacterial stains) and antifungal activities (against A. niger and C. albicans fungal strains). All the synthesized compounds exhibited moderate-to-potent antimicrobial activities. Conclusions: All the synthesized compounds exhibited moderate-to-potent antimicrobial activity

Computer-Aided Drug Design and Development: An Integrated Approach

Drug discovery and development is a very time- and resource-consuming process. Comprehensive knowledge of chemistry has been integrated with information technology to streamline drug discovery, design, development, and optimization. Computer-aided drug design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, and optimize the absorption, distribution, metabolism, excretion, and toxicity profile. Regulatory organizations and the pharmaceutical industry are continuously involved in the development of computational techniques that will improve the effectiveness and efficiency of the drug discovery process while decreasing the use of animals, cost, and time and increasing predictability. The present chapter will provide an overview of computational tools, such as structure-based and receptor-based drug designing, and how the coupling of these tools with a rational drug design process has led to the discovery of small molecules as therapeutic agents for numerous human disease conditions duly approved by the Food and Drug Administration. It is expected that the power of CADD will grow as the technology continues to evolve

Cyclodextrin - A Versatile Ingredient

The book is devoted to the highly versatile and potential ingredient Cyclodextrin, a family of cyclic oligosaccharides composed of ?-(1,4)-linked glucopyranose subunits. Its molecular complexation phenomena and negligible cytotoxic effects attribute toward its application such as in pharmaceuticals, cosmetics, food, agriculture, textile, separation process, analytical methods, catalysis, environment protection, and diagnostics. Efforts have also been made to concentrate on recent research outcomes along with future prospects of cyclodextrins to attract the interest of scientists from the industry and academia. The contributions of the authors are greatly acknowledged, without which this compilation would not have been possible

Taurine as a potential therapeutic agent interacting with multiple signaling pathways implicated in autism spectrum disorder (ASD): An in-silico analysis

Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations

3D-QSAR, molecular docking and ADME studies on indole analogues reveal antidepressant activity through monoamine oxidase-A inhibition

1012-1029Monoamine oxidase (MAO) enzymes over see the concentration of neurotransmitters and intracellular amines in the brain and peripheral tissues by catalysing their oxidative deamination and represents a crucial target in drug designing for the management of neurological and psychiatric disorders. Present study is an effort to present an economical fast high throughput screening easy method to identify indole analogues as potent MAO inhibitors, using different computational techniques. CoMSIA field-based 3D-QSAR models have been developed by applying the partial least squares regression algorithm that exhibit satisfactory predictive and descriptive capability with statistical parameters R² (0.9557) and Q² (0.8529). Generated model (s) helped in explaining the key descriptors firmly related with MAO inhibitory activity and are used to generate library of 1853 indole derivatives. Library is evaluated and has resulted in the identification of 30 indole derivatives with high docking scores (−9.978 to −7.136) in comparison to the antidepressant standard drug Isocarboxazid (−7.125). Further, these compounds have been scrutinized through drug-likeliness profiles and Desmond's molecular dynamics simulations studies for 100 ns. Further in vitro and in vivo studies on these molecules might provide us with new drug candidate for the treatment of depression with high therapeutic index

Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents

Non-steroidal anti-inflammatory drugs (NSAIDs) have been successfully used for the alleviation of pain and inflammation in the past and continue to be used daily by millions of patients worldwide. However, gastrointestinal (GI) toxicity associated with NSAIDs is an important medical and socioeconomic problem. Local generation of various reactive oxygen species plays a significant role in the formation of gastric ulceration associated with NSAIDs therapy. Co-medication of antioxidants along with NSAIDs has been found to be beneficial in the prevention of GI injury. This paper describes the synthesis and biological evaluation of N-1-(phenylsulfonyl)-2-methylamino-substituted-1H-benzimidazole derivatives as anti-inflammatory analgesic agents with lower GI toxicity. Studies in vitro and in vivo demonstrated that the antioxidant activity of the test compounds decreased GI toxicity

Benign prostatic hyperplasia: An overview of existing treatment

Benign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms (LUTS). A better understanding of the prostate physiology, function, and pathogenesis has led to the development of promising agents, useful in the management of LUTS in men. The specific approach used to treat BPH depends upon number of factors like age, prostrate size, weight, prostate-specific antigen level, and severity of the symptoms. 5α-reductase inhibitors decrease the production of dihydrotestosterone within the prostate, which results in decreased prostate volume, increased peak urinary flow rate, improvement of symptoms, decreased risk of acute urinary retention, and need for surgical intervention. α1-adrenergic receptor (α1-AR) antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Clinical efficacy of either 5α-reductase inhibitor or α1-AR antagonist has been further improved by using combination therapy; however, long-term outcomes are still awaited. Many more potential new therapies are under development that may improve the treatment of BPH. This article gives a brief account of rationale and efficacy of different treatment options presently available in the management of BPH