Transition metal-free efficient synthesis of bis(indolyl)propynes (BIPs).

A transition metal-free approach has been devised for the synthesis of a variety of bis(indolyl)propyne (BIP) derivatives. The strategy involves an iodine-catalyzed cascade condensation of α,ß-unsaturated acetylenic aldehydes with diversely substituted indoles. The strategy was applicable to gram scale synthesis and a library of 50 molecules, which were afforded in good to excellent yields (up to 96%), was developed. The salient features of the reaction involve the synthesis of indole based privileged scaffolds in a short reaction time under transition metal-free conditions, with a wide substrate scope and excellent yields under ambient conditions.

In Silico and In Vivo Evaluation of Anti-Arthritic Effects of Bakuchiol from Psoralea corylifolia Seeds in Experimental Rat Model.

In the present investigation, we studied the anti-arthritic effects of bakuchiol via in silico and in vivo experiments. Molecular Docking studies carried out on COX-1 (PDB ID: 3N8Z), COX-2 (PDB ID: 4PH9) and TNF-α (PDB ID: 7JRA), proteins involved in inflammation in arthritis. Bakuchiol showed the maximum binding affinity for TNF-α with binding affinity score is -7.29 kcal/mol. In vivo antiarthritic effects were studied in arthritic female wistar rats model prepared by intradermal injection of freund's complete adjuvant. Our treatment showed that bakuchiol at 20 and 40 mg/kg exhibited significant anti-inflammatory effects(p< 0.001) showed by significant decrease in paw volume, paw diameter, spleen and thymus weight and increase in pain threshold and body weight in arthritic rat model. A significant decrease in hematological parameters such as total leukocyte count (TLC), platelet count, CRP and rheumatoid arthritis factor (RF)and increase in red blood cells count, ESR and hemoglobin further demonstrated that bakuchiol treatment suppresses the progression of adjuvant induced arthritis (AIA) in arthritic rat model. Histological analysis further revealed that bakuchiol ameliorates the pathological manifestations of AIA . In silico and in vivo results revealed that bakuchiol has the potential to be developed as potent antiarthritic agent.

The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives.

Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-ß and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.

RdRp (RNA-dependent RNA polymerase): A key target providing anti-virals for the management of various viral diseases.

With the arrival of the Covid-19 pandemic, anti-viral agents have regained center stage in the arena of medicine. Out of the various drug targets involved in managing RNA-viral infections, the one that dominates almost all RNA viruses is RdRp (RNA-dependent RNA polymerase). RdRp are proteins that are involved in the replication of RNA-based viruses. Inhibition of RdRps has been an integral approach for managing various viral infections such as dengue, influenza, HCV (Hepatitis), BVDV, etc. Inhibition of the coronavirus RdRp is currently rigorously explored for the treatment of Covid-19 related complications. So, keeping in view the importance and current relevance of this drug target, we have discussed the importance of RdRp in developing anti-viral agents against various viral diseases. Different reported inhibitors have also been discussed, and emphasis has been laid on highlighting the inhibitor's pharmacophoric features and SAR profile.

Development and characterisation of clobetasol propionate loaded Squarticles as a lipid nanocarrier for treatment of plaque psoriasis.

Aim: The aim of this project is to improve the therapeutic effectiveness, permeation and retention of clobetasol propionate in sebaceous glands by reporting the use of Squarticles as lipidic nanosystem.Methods: Homogenisation method is used for the formulation of Squarticles (nanoemulgel) which was characterised on the basis of size, polydispersity index (PDI), viscosity, spreadability, DSC, % in vitro release, in vitro skin permeation deposition studies, and in vivo studies, scanning electron microscopic (SEM) and physical storage stability studies were done at different temperature conditions, i.e. 4 ± 2 °C, 25 ± 2 °C and 45 ± 2 °C for a period of 6 months for drug and formulation.Result: The morphological characterisation of prepared nanoemulsion shows small spherical shape and uniform size distribution as observed in the Scanning electron microscopic (SEM), having mean size (240.5 ± 9.2) and mean size distribution (0.282 ± 0.03) and zeta potential (-51.21). The drug release from optimised nanoemulsion (F2) in PBS (pH 5.5) was approximately 84.24 ± 1.35%, nanoemulgel formulations showed the release of 66.83 ± 2.05% while marketed gel showed the release of 57.67 ± 1.63% after 24 h. The cumulative percentage retention of clobetasol propionate loaded nanoemulgel was 63 ± 1.28% which was more than the marketed formulation (23.12% ±0.54). Physical stability studies show that formulation is more stable in cold condition. Further, the stability of active ingredient in gel formulation was determined using HPLC which shows around 15 ± 0.84% of loss in its activity.Conclusion: The present work has demonstrated the use of Squarticles as a novel carrier for treatment of plaque psoriasis by enhancing the better permeation, increasing skin retention, and enhances the effect of drug. The study also shows that the formulation is more stable in cold condition.

Recent synthetic and medicinal perspectives of tryptanthrin.

Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.

Synthetic and medicinal perspective of thiazolidinones: A review.

In the modern scenario, thiazolidinone scaffold has emerged as a very potent scaffold as per its clinical significance concerned. It has attracted the keen interest of the researchers due to its great diversity in biological activities. Thiazolidinones are the saturated form of thiazole, called thiazolidine with a carbonyl group. The 1,3-thiazolidin-4-ones possess wide range of pharmacological activities such as anti-cancer, anti-diabetic, anti-microbial, anti-viral, anti-inflammatory and anti-convulsant. In the past few years, various newer synthetic approaches have been designed to synthesize diverse scaffolds to explore the various types of biological activities. In this review, an attempt has been made by the authors to summarize various synthetic strategies for thiazolidinone derivatives as well as their biological significance.

Water-Promoted Regiospecific Azidolysis and Copper-Catalyzed Azide-Alkyne Cycloaddition: One-Pot Synthesis of 3-Hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones.

An efficient, eco-friendly, base free, one-pot, sequential protocol was developed for epoxide azidolysis and copper-catalyzed azide-alkyne cycloaddition using water as the solvent for the synthesis of 3-hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones. The optimized reaction conditions have been generalized in the case of aromatic as well as aliphatic alkyne partners to afford good yields and high regioselectivity.

Natural product inspired design and synthesis of ß-carboline and γ-lactone based molecular hybrids.

ß-Carboline and γ-lactone moieties have been selected by nature as privileged scaffolds and display a wide range of pharmacological properties. Following nature, we envisaged the preparation of new ß-carboline and γ-lactone based molecular hybrids incorporating both the pharmacophores. In this regard, a water-assisted In-mediated environmentally benign and easy to execute single-step tandem Barbier type allylation-lactonisation process has been devised in order to afford the targeted molecular architectures. It is anticipated that aqueous medium plays the key role in allylation as well as in the subsequent lactonisation process for the diastereo-selective synthesis of these conjugates. It is believed that water drives the reaction pathway through dual activation, it increases the electrophilic character of formyl and ester functionalities and simultaneously enhances the nucleophilic potential of the hydroxyl group to facilitate the in situ intramolecular condensation. Importantly, during this synthetic strategy no column chromatographic purification was required at any stage.

Riociguat as a treatment regime for pulmonary arterial hypertension: a review.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition distinguished by elevated pressure of pulmonary arteries and increased vascular resistance. The management of patients with PAH and CTEPH has advanced rapidly over last decade but despite the progress in the treatment, the survival of suffering patients remain unsatisfactory and there is no cure for the diseases. However, surgery is not a first choice for patients. Furthermore, some patients who undergo surgery have persistent pulmonary hypertension (HTN) as a side effect after surgery. Therefore, the search for an "ideal" therapy still goes on and it lead to the approval of riociguat as a potential agent for the treatment. It acts directly on soluble guanylate cyclase, exciting the enzyme, and elevating sensitivity to lower levels of NO. Riociguat, therefore, has potential as a novel therapy for PAH and CTEPH. This review is focused on various aspects of the recently approved "riociguat" including its efficacy and safety profiles with the clinical data highlighting its importance in the present scenario.

Recent advances in the chemistry and biology of benzothiazoles.

Benzothiazole is a privileged heterocyclic scaffold having a benzene ring fused with a five-membered thiazole ring. This moiety has attracted considerable attention because of its wide range of pharmacological activities such as antitubercular, antimicrobial, antimalarial, anticonvulsant, anthelmintic, analgesic, anti-inflammatory, antidiabetic, antitumor activity, etc. In the last few years, some novel benzothiazoles have been developed with varied biological activities. To access this scaffold in high yield and to introduce diversity, a variety of new synthetic methods have been invented. In this review, we highlight the development of novel benzothiazoles for various biological activities along with the best synthetic protocols for their synthesis.

Design, synthesis and ex-vivo release studies of colon-specific polyphosphazene-anticancer drug conjugates.

Colon-specific azo based polyphosphazene-anticancer drug conjugates (11-18) have been synthesized and evaluated by ex-vivo release studies. The prepared polyphosphazene drug conjugates (11-18) are stable in acidic (pH=1.2) buffer which showed that these polymer drug conjugates are protected from acidic environment which is the primary requirement of colon specific targeted drug delivery. The ex-vivo release profiles of polyphosphazene drug conjugates (11-18) have been performed in the presence as well as in the absence of rat cecal content. The results showed that more than 89% of parent drugs (methotrexate and gemcitabine) are released from polymeric backbone of polyphosphazene drug conjugates (14 and 18) having n-butanol (lipophilic moiety). The in-vitro cytotoxicity assay has also been performed which clearly indicated that these polymeric drug conjugates are active against human colorectal cancer cell lines (HT-29 and COLO 320 DM). The drug release kinetic study demonstrated that Higuchi's equation is found to be best fitted equation which showed that release of drug from polymeric backbone as square root of time dependent process based on non-fickian diffusion. Therefore, the synthesized polyphosphazene azo based drug conjugates of methotrexate and gemcitabine are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects.

Natural product-loaded lipid-based nanocarriers for skin cancer treatment: An overview.

The skin is essential for body protection and regulating physiological processes. It is the largest organ and serves as the first-line barrier against UV radiation, harmful substances, and infections. Skin cancer is considered the most prevalent type of cancer worldwide, while melanoma skin cancer is having high mortality rates. Skin cancer, including melanoma and non-melanoma forms, is primarily caused by prolonged exposure to UV sunlight and pollution. Currently, treatments for skin cancer include surgery, chemotherapy, and radiotherapy. However, several factors hinder the effectiveness of these treatments, such as low efficacy, the necessity for high concentrations of active components to achieve a therapeutic effect, and poor drug permeation into the stratum corneum or lesions. Additionally, low bioavailability at the target site necessitates high doses, leading to skin irritation and further obstructing drug absorption through the stratum corneum. To overcome these challenges, recent research focuses on developing a medication delivery system based on nanotechnology as an alternative to this traditional approach. Nano-drug delivery systems have demonstrated great promise in treating skin cancer by providing a more effective means of delivering drugs with better stability and drug absorption. An overview of various lipid-based nanocarriers is given in this review article that are utilized to carry natural compounds to treat skin cancer.

Characterization of immunologic properties of a second HLA-A2 epitope from a granule protease in CML patients and HLA-A2 transgenic mice.

The serine proteases, neutrophil elastase (HNE) and proteinase 3 (PR3), are aberrantly expressed in human myeloid leukemias. T-cell responses to these proteins have been correlated with remission in patients with chronic myeloid leukemia (CML). Human PR3/HNE-specific CD8(+) T cells predominantly recognize a nonameric HLA-A2-restricted T-cell epitope called PR1 which is conserved in both Ags. However, CML patients have CD8(+) T cells in peripheral blood recognizing an additional HLA-A2 epitope termed PR2. To assess immunologic properties of these Ags, novel recombinant vaccinia viruses (rVV) expressing PR3 and HNE were evaluated in HLA-A2 transgenic (Tg) mice (HHDII). Immunization of HHDII mice with rVV-PR3 elicited a robust PR3-specific CD8(+) T-cell response dominated by recognition of PR2, with minimal recognition of the PR1 epitope. This result was unexpected, because the PR2 peptide has been reported to bind poorly to HLA. To account for these findings, we proposed that HHDII mice negatively selected PR1-specific T cells because of the presence of this epitope within murine PR3 and HNE, leading to immunodominance of PR2-specific responses. PR2-specific splenocytes are cytotoxic to targets expressing naturally processed PR3, though PR1-specific splenocytes are not. We conclude that PR2 represents a functional T-cell epitope recognized in mice and human leukemia patients. These studies are registered at www.clinicaltrials.gov as NCT00716911.

Design, synthesis and ex vivo evaluation of colon-specific azo based prodrugs of anticancer agents.

Colon-specific azo based prodrugs of anticancer agents like methotrexate (6), gemcitabine (7) and analogue of oxaliplatin (RTB-4) (8) were synthesized and characterized by modern analytical techniques. The prepared prodrugs were stable in acidic (pH 1.2) and basic (pH 7.4) buffers which showed their stability in upper GIT environment. Further, an assay was performed which demonstrated the presence of azoreductase enzyme in the rat fecal material, rat cecum content and other parts of intestinal content which reduce specifically the azo bond and release the drug. The in vitro cytotoxicity assay was also performed which clearly indicated that these azo based prodrugs are active against human colorectal cancer cell lines (COLO 205, COLO 320 DM and HT-29). The release behavior of prodrugs (10, 11 and 15) was 60-70% after 24h incubation at 37°C. Therefore, the synthesized azo linked prodrugs of methotrexate, gemcitabine and RTB-4 are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects.

2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: in vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action.

Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) monophosphate prodrug (FMCAP) was synthesized and evaluated for its in vitro anti-HBV potency against a lamivudine-entecavir resistant clone (L180M+M204V+S202G). FMCA demonstrated significant antiviral activity against wild-type as well as lamivudine-entecavir resistant triple mutant (L180M+M204V+S202G). The monophosphate prodrug (FMCAP) demonstrated greater than 12-fold (12×) increase in anti-HBV activity without increased cellular toxicity. Mitochondrial and cellular toxicity studies of FMCA indicated that there is no significant toxicity up to 100 µM. Mode of action studies by molecular modeling indicate that the 2'-fluoro moiety by hydrogen bond as well as the Van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug-resistant mutants.

OSADHI - An online structural and analytics based database for herbs of India.

The current study aims to develop a PAN India database of medicinal plants along with their phytochemicals and geographical availability. The database consists of 6959 unique medicinal plants belonging to 348 families which are available across 28 states and 8 union territories of India. The database sources the information on four different sections - traditional knowledge, geographical indications, phytochemicals, and chemoinformatics. The traditional knowledge reports the plant taxonomy with their vernacular names. A total of 27,440 unique phytochemicals associated with these plants were curated from various sources in this study. However, due to the non-availability of general information like IUPAC names, InChI key, etc. from reliable sources, only 22,314 phytochemicals have been currently reported in the database. Various analyses have been performed for the phytochemicals which include analysis of physicochemical and ADMET properties calculated from open-source web servers using in-house python scripts. The phytochemical data set has also been classified based on the class, superclass, and pathways respectively using NPClassifier, a deep learning framework. Additionally, the antiviral potency of the phytochemicals was also predicted using two machine learning models - Random Forest and XGBoost. The database aims to provide accurate and exhaustive data of the traditional practice of medicinal plants in India in a single platform integrating and analyzing the rich customary practices and facilitating the development and identification of plant-based therapeutics for a variety of diseases. The database can be accessed at https://neist.res.in/osadhi/.

Identifying novel putative ERK1/2 inhibitors via hybrid scaffold hopping -FBDD approach.

ERK inhibitors are continuously explored by the researchers due to their clinical significance in resistant tumor cell lines. Though many ERK1/2 inhibitors are reported, there is still need to identify novel hits to increase the number of molecules in clinical trials. Therefore, an urgent need is to examine the existing chemical space for ERK inhibitory potential with an aim to develop novel scaffolds which can act as potent ERKs inhibitors. In this study, Ulixertinib, a known ERK2 inhibitor was selected to perform scaffold hopping to discover new scaffolds with similar binding mode followed by molecular docking analysis of the hits with highest similarity score to determine, both the binding mode and affinity in the catalytic domain of ERK2. The top hit was then subjected to FBDD to identify side chains which could enhance the binding affinity in the catalytic domain of ERK2. Again, docking analysis was performed to validate and determine their binding affinity. Further the top hit identified after docking analysis was subjected to molecular dynamic simulations. Overall, 3 hits (ligand 6, 8 and 10) were found to possess optimum pharmacodynamic and pharmacokinetic profile, in-silico, to be claimed as putative ERK2 inhibitors. This study disclosed new lead molecules with putative ERK2 inhibitory potential which may be further validated via biological evaluation.

Prospects of Treating Prostate Cancer through Apalutamide: A Mini-Review.

BACKGROUND: Prostate cancer is considered the second most diagnosed cancer, and one of the most common causes of death from cancer in men. Apalutamide is an effective, safe, and well-tolerated agent used for the treatment of men with non-metastatic Castration-Resistant Prostate Cancer (nmCRPC) and metastatic Hormone-Naive Prostate Cancer (mHNPC). Androgen receptor signaling is a leading factor that drives these prostate tumors. USFDA has approved apalutamide on 14 February 2018 as an agent that targets androgen receptor signaling through inhibition causing significant improvement in metastasis-free survival in patients with prostate cancer. OBJECTIVE: In this review, various aspects related to apalutamide have been summarized which involve the mechanism of action, chemistry, synthesis, pharmacokinetics, pharmacodynamics, adverse reactions, and safety parameters. METHODS: The literature was thoroughly searched in the relevant databases to identify studies published in this field during recent years. Special attention has been given to apalutamide clinical trials phases and its promising future as one of the first-line agents for the treatment of patients with advanced prostate cancer. RESULTS: Ongoing trials are progressing for apalutamide monotherapy and also for its combinations in other disease settings. The expected results of such trials will shape the future scenario of prostate cancer therapy. CONCLUSION: This review article has highlighted different aspects of Apalutamide like its mechanism of action, adverse effects, pharmacokinetics, pharmacodynamics, clinical trials among others. The contents of this article should make an excellent read for prospective researchers in this field.

North East India medicinal plants database (NEI-MPDB).

The rich biodiversity of North East India is one of the recognized biodiversity hotspots of the world. This region comprises of eight states (Assam, Arunachal Pradesh, Manipur, Meghalaya, Mizoram, Nagaland, Sikkim, and Tripura) with diverse ethnic communities having invaluable traditional knowledge/practices, passed through genesis. The medicinal plants in this region are rich in natural products/phytochemicals and have been used extensively by pharmaceutical industries. The present study is an attempt to develop a comprehensive resource of the medicinal plants with a quantitative analysis of the phytochemicals which can enhance knowledge on therapeutic indications and contribute in drug discovery and development. The database is a collection of 561 unique plants comprising of 9225 phytochemicals. The physiochemical properties of the phytochemicals were analyzed using indigenous python scripts whereas for the ADMET properties, open access servers were used. The data available in NEI-MPDB will help to connect the cutting-edge approach of various research groups and will help to translate the information into economic wealth by the pharmaceutical industries. The database is openly accessible at https://neist.res.in/neimpdb/.