Advancement in chiral heterocycles for the antidiabetic activity.

For the synthesis and development of pharmaceuticals, chirality is an important structural component. Chiral heterocyclic compounds have annoyed the interest of synthetic chemists who are working to create useful and efficient techniques for these molecules. As indicated by the expanding number of chiral drugs created in the last two decades, the link between chirality and pharmacological activity has become more important in the pharmaceutical and biopharmaceutical industries. Approximately 65% of currently used drugs are chiral, and many of them are promoted as racemates in many circumstances. There are a growing number of new chiral heterocyclic compounds with important biological properties and intriguing uses in medical chemistry and drug discovery. In this study, we review current breakthroughs in chiral heterocycles and their different physiological activities that have been published in the last year (from 2010 to early 2023). This study focuses on the current trends in the use of chiral heterocycles in drug design and the creation of several powerful and competent candidates for diabetic illnesses.

Halogen substituted aurones as potential apoptotic agents: synthesis, anticancer evaluation, molecular docking, ADMET and DFT study.

A series of halogen-substituted aurone derivatives (2a-k) were synthesized and evaluated for an anti-proliferative study against NCI 60 cancer cell line panel and showed that most of the compounds predominantly exhibited promising activity against MCF-7. Compound 2e exhibited promising anticancer activity against the MCF-7 cancer cell line with 84.98% percentage growth inhibition in a single dose assay of 10 µM with an IC50 value of 8.157 ± 0.713 µM. In apoptotic assay, the effect of compound 2e on the cell cycle progression indicated that exposure of MCF-7 cells to compound 2e induced a significant disruption in the cell cycle profile including a time-dependent decrease in the cell population at G0/G1 and G2/M phase and arrests the cell cycle at the S phase. In silico, molecular docking ADME and toxicity studies of all compounds were also carried out. The docking study revealed that all the aurone derivatives displayed good docking scores ranging from -7.066 to -8.573. The results of Molecular Electrostatic Potential Mapping (MESP) and Density Functional Theory (DFT) studies of the most active compound 2e and least active compound 2k also favoured the experimental results.

Cardioprotective Activity of Cassia fistula L. Bark Extract in Isoproterenol-Induced Myocardial Infarction Rat Model.

Cassia fistula Linn, generally recognized as Indian laburnum, is one of the ancient trees in the Indian subcontinent used for its ornamental and diverse medicinal properties. It is known for its ethnic medicinal uses in inflammatory and infectious pathologies such as antihelmintic, purgative, carminative, antipyretic, expectorant, analgesic, laxative, antiseptic, and antidote against snake poison. The Cassia bark is rich in anthraquinones, flavanols glycosides, and sitosterols, which renders it cardioprotective properties. The existing experiments were designed to assess the potential of Cassia fistula bark against isoproterenol (ISP)-induced cardiotoxicity in rats, which has not been validated yet. The bark was successively extracted with five different solvents, and each extract was subjected to in vitro antioxidant studies. Further acute oral toxicity assays were carried out preceding in vivo myocardial studies. Cardiotoxicity-inducing agent, ISP, was administrated to the rats for two consecutive days (8th and 9th). Based on in vitro studies, the Cassia fistula methanolic extract (CFME) was administered in two doses: CFME-LD (lower dose 250 mg/kg) and CFME-HD (high dose 500 mg/kg) separately. It was found that CFME produced a substantial decrease in lipid peroxidation and an increase in antioxidants in myocardial tissues. CFME abrogated the levels of triglyceride and total cholesterol with a decrease in alanine transaminase (ALT) and aspartate transaminase (AST) activity in serum at both doses. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and histopathology also revealed the protective effects of CFME against ISP-induced myocardial infarction. The study showed the significant role of the CFME as a strong antioxidant and cardioprotective action in ISP-induced toxicity.

Orally administered solasodine, a steroidal glycoalkaloid, suppresses ovalbumin-induced exaggerated Th2-immune response in rat model of bronchial asthma.

Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1ß, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.

In-silico Validation of the Proposed Treatment Strategy of Periodontitis.

OBJECTIVE: The present study aims to assess a proposed treatment approach or therapy for periodontitis by using the in-silico technique. The proposed treatment strategy offers a singular vehicular system consisting of minocycline (antibiotic), celecoxib (selective COX-II inhibitor), doxycycline hyclate (matrix metalloproteinase inhibitor), and hydroxyapatite (osteogenic agent). MATERIAL AND METHODS: Molecular docking studies of drugs were performed using Maestro version 9.4 software Schrödinger, and 3-Dimensional Crystallographic X-ray protein structures of targeted proteins were downloaded from RCSB protein data bank in .pdb file format. These agents were docked, and their affinities towards the receptors/protein/enzyme were calculated. Furthermore, their affinities were compared with the standard drug. RESULTS: The study suggests that minocycline and metronidazole possess equal affinity towards the RGPB and Inlj protein of P.gingivalis. Celecoxib, a well-known inhibitor of the COX-II enzyme, showed very high affinity. Selective inhibitor of MMP-8 possessed higher affinity than doxycycline, whereas CMT-3 showed equal affinity as doxycycline for MMP-13. Similarly, hydroxyapatite and simvastatin also showed a comparatively similar affinity for osteopontin receptor. CONCLUSION: Based upon molecular docking results, it can be concluded that the proposed treatment strategy would be a suitable approach for periodontitis and all the selected therapeutic agents have potential similar to the standard drugs, thereby constituting a reliable system for periodontitis.

Essential Oils as Potential Source of Anti-dandruff Agents: A Review.

BACKGROUND: Dandruff is a frequent occurring scalp problem that causes significant discomfort to approximately 50% population at some stage of life, especially post-puberty and preadult age. OBJECTIVES: In this review, we aim to summarise the recent findings regarding anti-fungal properties of herbal essential oils against pathogens involved in dandruff prognosis. METHODS: A literature search of studies published between 2000 and 2020 was conducted over databases: PubMed, Google Scholar, Scopus, and Science Direct. Literature was explored using the guidelines given in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Dandruff, characterised by clinical symptoms of dryness, pruritis, scaly, and flaky scalp, is considered as a primary manifestation of seborrheic dermatitis. Amongst various etiological and pathophysiological factors, significant role of yeasts, primarily, species of Malassezia, Candida, has been strongly correlated with dandruff, while incidences of M. furfur, M. restricta and M. globosa are high compared to others. Due to relapse of symptoms with withdrawal of conventional anti-dandruff products, patients find best alternatives in natural products. Essential oils of herbal origin such as tea tree oil, lime oil, rosemary oil, have gained global importance in dermatology. These oils are rich in aromatic secondary metabolites, especially terpenes and phenolic components that impart substantial antimicrobial properties and resisting biofilm production. CONCLUSION: On the basis of the available information, we can conclude that essential oils have huge potential to be developed as anti-dandruff products, however, further studies are warranted to establish their efficacy in dandruff cure.

Heterocyclic Moieties as HDAC Inhibitors: Role in Cancer Therapeutics.

'Epigenetic' regulation of genes via post-translational modulation of proteins is a wellexplored approach for disease therapies, particularly cancer chemotherapeutics. Histone deacetylases (HDACs) are one of the important epigenetic targets and are mainly responsible for balancing the acetylation/deacetylation of lysine amino acids on histone/nonhistone proteins along with histone acetyltransferase (HAT). HDAC inhibitors (HDACIs) have become important biologically active compounds for the treatment of cancers due to cell cycle arrest, differentiation, and apoptosis in tumor cells, thus leading to anticancer activity. Out of the four classes of HDAC, i.e., Class I, II, III, and IV, HDACIs act on Class IV (Zinc dependent HDAC), and various FDA-approved drugs belong to this category. The required canonical pharmacophore model (zinc-binding group, surface recognition cap, and appropriate linker) supported by HDACIs, various heterocyclic moieties containing compounds exhibiting HDAC inhibitory activity, and structure-activity relationship of different synthetic derivatives reported during the last twelve years have been summarized in this review.

Clerodendrum serratum extract attenuates production of inflammatory mediators in ovalbumin-induced asthma in rats.

In the present study, ethanolic extract of Clerodendrum serratum roots was investigated for its potential to reverse some features of bronchial asthma in ovalbumin-induced murine model of asthma. Clerodendrum serratum commonly called bharangi, (family Solanaceae) is a well-known anti-allergic drug in Asian folk system of medicines. In the present work, pharmacological studies are done to provide scientific evidence for therapeutic potential of plant in allergic asthma. Asthma was induced in experimental rats with allergen suspension of ovalbumin and aluminum hydroxide followed by treatment with dexamethasone (2.5 mg/kg, po) or C. serratum root extract (0.53 and 5.3 mg/kg, b. w., po). Biomarkers of inflammatory response including cell counts, immunoglobulin E, cytokines such as interleukin (IL) -4, -5, -1ß, tumor necrosis factor-α (TNF-α), leukotriene (LTD-4), and nitrite concentration in blood as well as bronchial (BAL) fluid were tested. Lung functions in asthmatic and treated animals were evaluated as breathing rate and tidal volume. Treatment with C. serratum extract markedly (p < 0.001, p < 0.01, and p < 0.05) diminished infiltration of inflammatory cells, IgE, cytokines, and nitrites in blood serum and bronchial fluid. Improvement in lung functions (p < 0.05) of asthmatic animals after CSE treatment also supports our findings. Results of the study suggest therapeutic potential of C. serratum in allergic asthma that can be related to ability of plant to attenuate response of inflammatory cells and thereby, production of inflammatory and proinflammatory cytokines in airways.

Synthesis, ADMET prediction and reverse screening study of 3,4,5-trimethoxy phenyl ring pendant sulfur-containing cyanopyrimidine derivatives as promising apoptosis inducing anticancer agents.

Cancer remains considered as one of the leading global health problems either due to meagre and suboptimal therapeutic response of chemotherapeutic agents or due to the emergence of spontaneous complex multidrug resistance in cancer cells. This created a persistent need for the development of new anticancer agents. Enthralled by the high success rate for natural product-based drug discovery and current research scenario, we synthesized a new series of 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivatives clubbed with different amines intending to search an anticancer lead compound. To probe the anti-proliferative spectrum of the synthesized derivatives, an in-vitro evaluation was piloted against a panel of 60 cancer cell lines at the National Cancer Institute (NCI) representing major types of cancer diseases. Most of the derivatives showed good to moderate anti-proliferative activity. The results revealed that compound 4e displayed the most promising broad-spectrum anticancer activity with high growth inhibition of various cell lines representing multiple cancers diseases. Mechanistic investigation of compound 4e in human breast cancer MDA-MB-231 cells showed that compound 4e triggers cell death through the induction of apoptosis. ADMET studies and reverse screening were also performed to identify the potential targets of designed molecules. It was concluded that 3,4,5-trimethoxy phenyl ring pendant sulfur-containingcyanopyrimidine derivative 4e could act as a promising hit molecule for further development of novel anticancer therapeutics.

Combretastatin-based compounds with therapeutic characteristics: a patent review.

Introduction: Combretastatins represent a potent class of phenolic-stilbene natural products that function as colchicine binding site inhibitors of tubulin polymerization and have been advanced as promising anticancer lead compounds. Among them, combretastatin A-4 is the most potent lead molecule due to its broad spectrum cytotoxicity against a variety of tumors. However, low water solubility due to its high lipophilic nature and inter-conversion of olefinic double bond from more active cis to less active trans-conformation poses limitations to its clinical utility. However, different approaches including prodrugs, salt formations, structural modifications, prevention of inter-conversion of the olefinic bond and changes to the substitution pattern on the rings of combretastatin A-4 were investigated and successfully resulted in different combretastatin-based molecules that demonstrated varying levels of potency against different types of tumors during their in-vitro and in-vivo studies. Areas covered: This review covers the patents over a period of 2008-2018. Expert opinion: Molecular hybridization and prodrug designing imparted multi-targeted actions to combretastatin derivatives. Currently, various combretastatin derivatives are under clinical trials. These derivatives could be used to treat disorders other than cancer, due to their vascular disrupting action.

Revealing quinquennial anticancer journey of morpholine: A SAR based review.

Morpholine, a six-membered heterocycle containing one nitrogen and one oxygen atom, is a moiety of great significance. It forms an important intermediate in many industrial and organic syntheses. Morpholine containing drugs are of high therapeutic value. Its wide array of pharmacological activity includes anti-diabetic, anti-emetic, growth stimulant, anti-depressant, bronchodilator and anticancer. Multi-drug resistance in cancer cases have emerged in the last few years and have led to the failure of many chemotherapeutic drugs. Newer treatment methods and drugs are being developed to overcome this problem. Target based drug discovery is an effective method to develop novel anticancer drugs. To develop newer drugs, previously reported work needs to be studied. Keeping this in mind, last five year's literature on morpholine used as anticancer agents has been reviewed and summarized in the paper herein.

Green recipes to quinoline: A review.

The quinoline core possesses a vast number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antitubercular and antileishmanial. The conventional classical synthetic methods require the use of expensive and harsh conditions such as high temperature. Currently the scientific communities are searching new methodology to eliminate the use of chemicals, solvents and catalysts, which are hazardous to human health as well as to environment. This review provides a concise overview of new dimensions of green chemistry approaches in designing quinoline scaffold that would encourage the researchers towards green chemistry as well as future application of these greener, non-toxic, environment friendly methods in designing quinoline scaffold.

Antidiabetic activity of hydro-alcoholic stem bark extract of Callicarpa arborea Roxb. with antioxidant potential in diabetic rats.

BACKGROUND: Despite the availability of synthetic antidiabetic drugs, diabetes mellitus is still affecting millions of people with increasing rate of disease incidence and mortality throughout the world. Ethnomedicinal survey documents the traditional usefulness of Callicarpa arborea Roxb. stem bark in the management of diabetes mellitus. MATERIALS AND METHODS: In our study, hydro-alcoholic extract (HAE) of Callicarpa arborea stem bark was prepared according to WHO guidelines for herbal drugs, and screened for antidiabetic activity in streptozotocin (STZ)-induced diabetic rats. Acute oral toxicity and in vitro antioxidant activity studies along with phytochemical analyses of HAE were also carried out. RESULTS: Acute oral toxicity study indicated that HAE was safe up to a dose of 2000mg/kg body weight of rats. Results of antidiabetic activity study revealed that HAE of C. arborea stem bark possesses significant (p<0.05) hypoglycemic activity compared to normal control group in experimental rats. Histological observations of treated pancreas and liver tissues confirmed the antidiabetic efficacy of HAE. In antioxidant activity, HAE exhibited significant radical scavenging activity. CONCLUSION: From results, it can be concluded that HAE of C. arborea stem bark may have possible role as herbal antioxidants in the prevention and/or treatment of oxidative stress-induced diabetes mellitus. The antioxidant property of plant phenolic and flavonoid contents present in HAE might be responsible for the antidiabetic efficacy of C. arborea stem bark.

Design, virtual screening and docking study of novel NS3 inhibitors by targeting protein-protein interacting sites of dengue virus - a novel approach.

Currently dengue is a serious disease which has become a global burden in the last decade. Unfortunately, there are no effective drugs and vaccines against this disease. DENV non-structural protein (NS) 3, which is viral protease which is a potential target for antiviral therapy. Targeting this we performed homology modeling and protein-protein docking study of NS3 with NRBP (Nuclear Receptor Binding Protein) of human as it has been proved that NS3 of DENV interacts with NRBP which causes cellular trafficking in human cell. To carry out search of novel DENV protease inhibitors by in silico screening panduratin molecule was selected. 65 novel compounds were designed which involved substituting positions 1-5 of the benzyl ring A (4hydroxy-panduratinA) with various substituents. The protein-protein docking showed that the aminoacid residues of NS3 which were interacting with NRBP were found to be Ala 325, Asp 324, Phe 326, Asp 335, Glu 336, Glu 328, Asp 485, Gln 478, Arg 459, Gly 446 and Leu 480. These residues were targeted by the ligands which showed excellent binding affinity as binding energy. The ligand PKP10 showed lowest binding energy. It is also observed that the interface residues participated in the protein-protein interaction are being inhibited by the ligands.