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.

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/.

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/.

Applying polypharmacology approach for drug repurposing for SARS-CoV2.

Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CLpro, PLpro, RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail. Graphical abstract: Drug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary Information: The online version contains supplementary material available at 10.1007/s12039-022-02046-0.

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.

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.

Multi-Target Directed Ligands (MTDLs): Promising Coumarin Hybrids for Alzheimer's Disease.

Alzheimer's disease (AZD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cognitive domains, including executive function. The progression of AZD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AZD include a decreased concentration of acetylcholine (ACh), deposition of amyloid-ß (Aß) peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AZD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid molecules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffold have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aß aggregation. In the present review, we have focused on different reported coumarin hybrids as multi-target-directed agents against AZD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hydroxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hybrids, important clinical investigations and the structure-activity relationship have also been discussed in this compilation.

Vitamin D and immuno-pathology of COVID-19: many interactions but uncertain therapeutic benefits.

Introduction: COVID-19 pandemic has caused huge loss of human lives and extensive socio-economic damages. The immuno-pathology of this disease is neither clearly understood nor there are effective drugs for severe cases of COVID-19. Repurposing of available drugs for the treatment of COVID-19 is imperative.Areas Covered: This review has gathered the evidence from PubMed, Google Scholar, WHO, and other reliable websites on COVID-19 and summarized the existing knowledge of the immuno-pathology of COVID-19. We elucidated how vitamin D through its diverse actions on immune effector cells, epithelial cells, or renin-angiotensin-aldosterone system could have a modulatory role on the pathogenic mechanisms of COVID-19. The epidemiological evidence associating vitamin D deficiency with the severity and incidence of COVID-19 is also presented. However, the evidence of clinical benefit to patients of COVID-19 from randomized controlled trials with vitamin D has not come as yet.Expert opinion: It is now established that fatality of COVID-19 is primarily determined by hyperactivation of the host's innate immune system in response to SARS-CoV-2 invasion, and thus the research on the immuno-modulatory and other roles of vitamin D against viral infections should be pursued vigorously. This would be also useful for future pandemics caused by other novel viruses.

Recent Nanocarrier Approaches for Targeted Drug Delivery in Cancer Therapy.

Cancer is one of the most serious health concerns in the 21st century whose prevalence is beyond boundaries and can affect any organ of the human body. The conventional chemotherapeutic treatment strategies lack specificity to tumors and are associated with toxic effects on the immune system and other organ systems. In the past decades, there has been continuous progress in the development of smart nanocarrier systems for target-specific delivery of drugs against a variety of tumors, including intracellular gene-specific targeting. These nanocarriers are able to recognize the tumor cells and deliver the therapeutic agent in fixed proportions, causing no or very less harm to healthy cells. Nanosystems have modified physicochemical properties, improved bioavailability, and long retention in blood, which enhances their potency. A huge number of nanocarrier based formulations have been developed and are in clinical trials. Nanocarrier systems include polymeric micelles, liposomes, dendrimers, carbon nanotubes, gold nanoparticles, etc. Recent advancements in nanocarrier systems include mesoporous silica nanoparticles (MSNs), metal organic frameworks, and quantum dots. In the present review, various nanocarrier based drug delivery systems, along with their applications in the management of cancer, have been described with special emphasis on MSNs.

Synthetic and Medicinal Perspective of Fused-Thiazoles as Anticancer Agents.

BACKGROUND: Cancer is second leading disease after cardiovascular disease. Presently, Chemotherapy, Radiotherapy and use of chemicals are some treatments available these days. Thiazole and its hybrid compounds extensively used scaffolds in drug designing and development of novel anticancer agents due to their wide pharmacological profiles. Fused thiazole scaffold containing drugs are available in market as a promising group of anticancer agents. METHODS: The detailed study has been done using different database that focused on potent thiazole hybrid compounds with anticancer activity. The literature included in this review is focused on novel fused thiazole derivatives exhibiting anticancer potency in last decade. RESULTS: Literature suggested that thiazoles and its fused and linked congener serve excellent pharmacological profile as an anticancer agent. Various synthetic strategies for fused thiazole are also summarized in this article. Novel thiazole and its fused congener showed anticancer activity against various cancer cell lines. INTERPRETATION: Thiazole is a promising scaffold reported in literature with broad range of biological activities. This article covers the thiazole compounds fused with other carbocyclic/heterocycle including benzene, imidazole, pyridine, pyrimidine, quinoline, phenothiazine, thiopyrano, steroids, pyrrole etc. with anticancer activity from last decades. Several inhibitors for breast cancer, colon cancer, melanoma cancer, ovarian cancer, tubulin cancer etc. were reported in this review. Thus, this review will definitely aid to develop a lead for the new selective anticancer agents in future.

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.

Copanlisib: Novel PI3K Inhibitor for the Treatment of Lymphoma.

Lymphoma refers to a specialized category of blood cancers, which is characterized by lymph node enlargement, reduced body weight, prolonged tiredness, and fever associated with sweats. Traditional treatment strategies involve chemotherapy, radiation therapy, targeted therapy, and surgery. Copanlisib has emerged as a very potent drug which acts through inhibiting PI3K enzyme. The FDA has approved it for specific treatment of follicular Lymphoma in September 2017. Copanlisib induces tumor cell death along with the prevention of proliferation of dominant malignant ß-cells. Copanlisib has a large volume of distribution i.e., 871L (%CV 47.4), plasma protein binding up to 15.8%, plasma half-life(t1/2) of 39.1h and the mean systemic plasma clearance 18.9 L/h (%CV 51.2). In the present review, various aspects related to Copanlisib have been summarized, which include pathophysiology, synthetic strategy, pharmacokinetics, pharmacodynamics and clinical studies. A special emphasis is paid on various reported adverse effects and in silico/in vivo studies conducted on Copanlisib.

An update on chemical classes targeting ERK1/2 for the management of cancer.

Cancer, still in the limelight due to its dreadful nature, shows overexpression of multiple signaling macromolecules leading to failure of many chemotherapeutic agents and acquired resistance to chemotherapy. These factors highlight the significance of shifting toward targeted therapy in cancer research. Recently, ERKs (ERK1 and 2) have been established as a promising target for the management of various types of solid tumors, due to their aberrant involvement in cell growth and progression. Several ERKs inhibitors have reached clinical trials for the management of cancer and their derivatives are being continuously reported with noteworthy anticancer effect. This review highlights the recent reports on various chemical classes involved in the development of ERKs inhibitors along with their in vitro and in vivo activity and structure-activity relationship profile.

Agonist, antagonist and signaling modulators of ABA receptor for agronomic and post-harvest management.

Abscisic acid (ABA) is a ubiquitous phytohormone, plays important roles in several physiological processes, including stress adaptation, flowering, seed germination, fruit ripening, and leaf senescence etc. ABA binds with START domain proteins called Pyrabactin Resistance1 (PYR1)/PYR1-like (PYL)/Regulatory Components of ABA Receptors (RCARs) and controls the activity of PP2C phosphatase proteins and in turn the ABA-dependent signaling pathway. Fourteen ABA receptors have been identified in the model plant Arabidopsis thaliana and have shown to be involved in various biological functions. Under field conditions, exogenous application of ABA produces inadequate physiological response due to its rapid conversion into the biologically inactive metabolites. ABA shows selective binding preferences to PYL receptor subtypes and hence produces pleiotropic physiological and phenotypic effects which limit the usage of ABA in agriculture. An agrochemical meant for ameliorating the undesirable physiological effect of the plant should ideally have positive biological attributes without affecting the normal growth, development, and yield. Therefore, to overcome the limitations of ABA for its usage in various agricultural applications, several types of ABA-mimicking agents have been developed. Many compounds have been identified as having significant ABA-agonist/antagonist activity and can be employed to reverse the excessive/moderate ABA action. The present review highlights the potential usage of ABA signaling modulators for managing agronomic and postharvest traits. Besides, designing, development and versatile usage of ABA-mimicking compounds displaying ABA agonists and antagonist activities are discussed in detail.

Role of sulphur-heterocycles in medicinal chemistry: An update.

From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.

Coumarin Hybrids: Promising Scaffolds in the Treatment of Breast Cancer.

Breast cancer is the most common invasive cancer in women, and the second main cause of deaths in women, after lung cancer. There is continuous advancement in the development of therapeutic agents against breast cancer in recent years and it is still in progress. Development of hybrid molecules by combining different pharmacophores to obtain significant biological activity is an excellent approach. Coupling of coumarin scaffold with other distinct motifs has led to the design of newer compounds against breast cancer. These distinct pharmacophores possess a diverse mode of action as well as selectivity. It has been reported in the literature that coumarin hybrids possess significant potency against breast cancer by binding to various biological targets which are associated with breast cancer. Due to low toxicity profile on various organ systems, coumarin hybrids have nowadays attracted the keen attention of researchers to explore their therapeutic ability against breast cancer. Reported coumarin hybrids include coupling with isoxazole, thiazole, monastrol, chalcone, triazole, sulphonamide, triphenylethylene, benzimidazole, pyran, imidazole, stilbene, oestrogen, phenylsulphonylfuroxan, etc. In the present review, a description of various coumarin hybrid molecules has been presented along with their structural-activity relationships.

Diversity-Oriented Synthetic Approaches for Furoindoline: A Review.

The furo [2,3-b] indoline ring system is one of the most important structural units in various natural products. It has been known to have inherent biological activities and is utilized as a synthetic target for a number of natural compounds; therefore, this has contributed to a great demand for the growth of synthetic methods for this ring system. Most important compounds with furoindoline ring system are physovenine, madindoline A and B and makomotindoline etc. These compounds are well known to exhibit biological activity against different diseases such as glaucoma, cancer, cachexia, Castleman's disease, rheumatoid arthritis, etc. The current article focuses on various synthetic approaches for furoindoline containing compounds and essential furoindoline moiety, such as oxindole-5-O-tetrahydropyranyl ether route etc., and various other diastereoand enantio- controlled approach in a very concise way.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. METHODS: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. RESULT: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

Natural products and their derivatives as cyclooxygenase-2 inhibitors.

From ancient times, natural products have been continuously used as therapeutic agents in the treatment of various ailments. Many drugs from the natural origin are available in the market as potent medicines. Over expression of cyclooxygenase-2 (COX-2) enzyme is associated with various physical disorders like various types of inflammations associated with cardiovascular diseases or malignancies. The COX-2 inhibitory activity of many active constituents derived from plants is well established in the literature. These include coumarins, alkaloids, flavonoids, cinnamates, stilbenes and xanthines. In the present review, an attempt has been made to summarize applications of compounds since 2000 obtained from natural sources as COX-2 inhibitors. A brief synthetic methodology to access these natural product derivatives has been highlighted along with the Structure Activity Relationship (SAR).

Pyrrolopyrimidines: An update on recent advancements in their medicinal attributes.

Fused heterocycles are reported to demonstrate variety of biological activities such as anticancer, antibacterial, antifungal and anti-inflammatory, and are thus exhaustively utilized in the field of medicinal chemistry. Pyrrolopyrimidines is one of the major classes of fused heterocycles which are extensively reported throughout the literature. Several reports suggest that pyrrolopyrimidine as fused scaffold possess more diverse and potent pharmacological profile than individual pyrrole and pyrimidine nucleus. Different pathological targets require different structural attributes reflected via varied substitutions, thus in recent years, researchers have employed various synthetic strategies to achieve desired substitutions on the pyrrolopyrimidine nucleus. In this review, authors highlight the recent advancement in this area, special focus was laid on the pharmacological profile and structure-activity relationship studies (SAR) of various synthesized pyrrolopyrimidine derivatives.