Background Several anti-retroviral drugs are available against Human immunodeficiency virus type-1, but have multiple adverse side effects. Hence, there is an incessant compulsion for effectual anti-retroviral agents with minimal or no intricacy. Traditionally, natural products have been the most successful source for the development of new medications. Withania somnifera, also known as Ashwagandha, is the utmost treasured medicinal plant used in Ayurveda, which holds the potential to give adaptogenic, immunomodulatory, and antiviral effects. However, its effect on HIV-1 replication at the cellular level has never been explored. Herein, we focused on the anti-HIV-1 activity and the probable mechanism of action of hydroalcoholic and aqueous extracts of Withania somnifera roots and its phytomolecules. Methods The cytotoxicity of the extracts was determined through MTT assay, while the in vitro anti-HIV-1 activity was assessed in TZM-bl cells against the HIV-1 strains of X4 and R5 subtypes. Results were confirmed in peripheral blood mononuclear cells, using the HIV-1 p24 antigen assay. Additionally, the mechanism of action was determined through the Time of Addition assay, which was further validated through the series of enzymatic assays, i.e. HIV-1 Integrase, Reverse transcriptase, and Protease assays. To explore the role of the identified active metabolites of Withania somnifera in antiretroviral activity, molecular docking analyses were performed against these key HIV-1 replication enzymes. Results The hydroalcoholic and aqueous extracts of Withania somnifera roots were found to be safer at the sub-cytotoxic concentrations and exhibited their ability to inhibit replication of two primary isolates of HIV-1 through cell-associated and cell-free assays, in dose-dependent kinetics. Several active phytomolecules found in Withania somnifera successfully established hydrogens bonds in the active binding pocket site residues responsible for the catalytic activity of HIV replication and therefore, signifying their role in the attenuation of HIV-1 infection as implied through the in silico molecular docking studies. Conclusions Our research identified both the hydroalcoholic and aqueous extracts of Withania somnifera roots as potent inhibitors of HIV-1 infection. The in silico analyses also indicated the key components of Withania somnifera with the highest binding affinity against the HIV-1 Integrase by 12-Deoxywithastramonolide and 27-Hydroxywithanone, HIV-1 Protease by Ashwagandhanolide and Withacoagin, and HIV-1 Reverse transcriptase by Ashwagandhanolide and Withanolide B, thereby showing possible mechanisms of HIV-1 extenuation. Overall, this study classified the role of Withania somnifera extracts and their active compounds as potential agents against HIV-1 infection.

Schizophrenia is a complex disorder whose etiology and pathogenesis is not completely understood. Schizophrenia is associated with increased activity at dopaminergic and serotoninergic receptor sites [1,2]. Dopamine D 2 occupancy is most important and required for an antipsychotic response. However, it has been proven that, extrapyramidal side effects are also increased with the increase of dopamine receptor occupancy above 80 % [3]. Some antipsychotic drugs like clozapine, olanzapine (fig. 1) have lower dopamine D 2 occupancy with faster dissociation from the receptor [4-6]. The newer atypical antipsychotics compounds have interaction with multiple receptor targets. These drugs act through blockade of several receptors like dopamine, serotonin (5HT), adrenergic, muscarinic and histamine receptors [7,8]. In the atypical antipsychotic activity, 5HT receptor acts as an important target [9]. The atypical antipsychotic agents possess 5HT 2A antagonistic activity along with D 2 receptor antagonistic activity and these targets are the basis for the design of newer potential atypical antipsychotic agents. These potential atypical antipsychotic agents have fewer side effects [10-12]. These new potential antipsychotics will provide knowledge about the molecular mechanisms of action and is important for understanding of the pathophysiology of schizophrenia and for design of new drugs with improved efficacy and fewer side effects than the existing ones. The aim of present work was to synthesize new molecule like chromen-2-one derivatives, which might act on D 2 receptors as well as 5HT receptor and evaluate their pharmacological action for atypical antipsychotic activity.

ÖZYeni ilaçların gelişimini hızlandırmak amacıyla Gıda ve İlaç İdaresi, Ocak 2006'da faz '0' klinik testleri olarak adlandırılan keşif amaçlı Yeni Araştırılan İlaç (YAİ) rehberinin oluşturulduğunu açıkladı. Kimya, üretim ve kontrol bilgilerinin yanı sıra klinik öncesi ve klinik yaklaşımların açıklığa kavuşturulması için tasarlanan bu rehber YAİ uygulaması altında, yakından ilişkili ilaçlar veya terapötik biyolojik ürünler ile ilgili çalışmalar da dahil olmak üzere insanlarda keşif çalışmaları planlanırken göz önüne alınmalıdır (21 CFR 312). Mevcut düzenlemeler, önerilen araştırmanın amaçlarına, önerilen özgül insan testlerine ve beklenen risklere bağlı olarak YAİ başvurusu ile gönderilmesi gereken veri miktarında büyük bir esneklik sağlar. Ajans, sponsorların bu esneklikten tam olarak yararlanmadığına ve genellikle YAİ'lerde düzenlemeler için gerekli olanlardan daha fazla destekleyici bilgi sağladığına inanmaktadır. Bu rehber, insanlarda sınırlı, erken keşif YAİ çalışmalarını planlarken hangi imalat kontrollerinin, klinik öncesi testlerin ve klinik yaklaşımların düşünülebileceğini açıklığa kavuşturmayı amaçlamaktadır. Anahtar kelimeler: YAİ, klinik öncesi testler, klinik testler, faz 0In a move to speed up the development of new medicines, the Food and Drug Administration announced in January 2006 the creation of the exploratory Investigational New Drug (IND), the so-called phase '0' clinical trials. This guidance is intended to clarify what preclinical and clinical approaches, as well as chemistry, manufacturing, and controls information, should be considered when planning exploratory studies in humans, including studies of closely related drugs or therapeutic biological products, under an IND application (21 CFR 312). Existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with an IND application, depending on the goals of the proposed investigation, the specific human testing proposed, and the expected risks. The agency believes that sponsors have not taken full advantage of that flexibility and often provide more supporting information in INDs than is required by regulations. This guidance is intended to clarify what manufacturing controls, preclinical testing, and clinical approaches can be considered when planning limited, early exploratory IND studies in humans.

Introduction: Mental disorders are very serious complicated disorders. Schizophrenia is one of the most baffling mental disorders. The new series 7-(2-(benzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2- 1(4a-4k) was synthesized in search of newer compounds for Schizophrenia. Methods: Synthesis is done by refluxing in dry pyridine with various substituted 2-amino benzothiazoles derivatives (3a-3k) and 7-(2-Chloroethoxy)-4-methyl-2H-chromen-2-one(2). The molecular docking approach was used to screen these generated derivatives. Chem Bio Draw Ultra 12 was used to draw the compounds, which were then exposed to all potential conformations of compounds interacting with receptors. The Glide 7.6, Schrodinger 2017 Maestro 11.3 was used to achieve molecular docking. The Dopamine receptor 6CM4 serotonin 5TUD PDBs were acquired from the database of Brookhaven Protein. Using the OPLS 2005 force field, the ligand-protein hydrogen-bond network was acquired, along with the overall energy reduced. A glide score was used to rate the docking poses. Results: The produced compounds have been identified with the use of analytical and spectral data. All of the produced substances were tested and analyzed for serotonin 5HT2 antagonistic and dopamine D2 activity, which can be considered as a measure of typical antipsychotic properties. Conclusion: Compounds 4b, 4c, 4e, 4g & 4i have demonstrated promising pharmacological action in preliminary studies. According to the preceding findings, compounds with electron-withdrawing substitutions, such as 4e & 4b, have a good atypical profile of antipsychotics

The present work deals with the formulation and development of oral herbal liquid dosage and its comparative study with marketed dosage for quality evaluation parameters. We have used different Poly-herbs for the formulation of syrup because they expressed high effectiveness in a vast number of diseases. As aforementioned the therapeutic effect of herbal medicines is exerted due to the presence of different constituents and the effects are further potentiated when compatible herbals are formulated together in PHFs (Poly-herbal formulations). PHF show compatible effect with those of standard allopathic drugs. We had tested its Quality control pre and post-formulation evaluation parameters. The Quality control tests for developed herbal syrup include: Physical appearance (Color, Odor, and Taste), Clarity tests, solubility tests, pH, Density, Viscosity, Specific gravity, Refractive index, FTIR study of active constituent used in herbal syrup. This syrup is also tested for acute oral toxicity study (LD50), Antioxidant activity by using Nitric oxide free radical scavenging method, and hepato-protective activity by using paracetamol-induced hepatotoxicity in rats. From the obtained results, we concluded that formulated poly-herbal syrup passed all quality control tests and also proved its effectiveness. The formulation F2 and F3 were the best poly-herbal formulation and it was selected for further study. In hepato-protective activity, F2 formulation when compared with the standard formulation of silymarin have shown good results.

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