Macromolecules: Synthesis, antimicrobial, POM analysis and computational approaches of some glucoside derivatives bearing acyl moieties.

Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2-8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 µg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ-, O'δ-) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.

Indazole-based microtubule-targeting agents as potential candidates for anticancer drugs discovery.

Tremendous research is focused on developing novel drug candidates targeting microtubules to inhibit their function in several cellular processes, including cell division. In this regard, several indazole derivatives were sought to target the colchicine binding site on the ß-tubulin, a crucial protein required to form microtubules, to develop microtubule targeting agents. Even though there are several reviews on the indazole-based compounds, none of them focused on using indazole scaffold to develop microtubule targeting agents. Therefore, this review aims to present the advances in research on compounds containing indazole scaffolds as microtubule targeting agents based on the articles published in the last two decades. Among the articles reviewed, we found that compounds 6 and 7 showed the lowest IC50 values of 0.6 âˆ¼ 0.9 nM in the cell line studies, making them the strongest indazole derivatives that target microtubules. The compounds 30, 31, 37 (IC50 = ∼ 1 nM) and compounds 8, 38 (IC50 = ∼ 2 nM) have proved to be potent microtubule inhibitors. The compounds 18, 31, 44, 45 also showed strong anticancer activity (IC50 = ∼ 8 nM). It is important to notice that except for compounds 9, 12, 13, 15, and SRF, the top activity compounds including 6, 7, 8, 10, 11, 30, 31, 37, 44, and 45 contain 3,4,5­trimethoxyphenyl substitution similar to that of colchicine. Therefore, it appears that the 3,4,5­trimethoxyphenyl substituent on the indazole scaffold is crucial for targeting CBS.

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective.

With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C7 H6 N2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles. The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

Developments in the HCV Screening Technologies Based on the Detection of Antigens and Antibodies.

Hepatitis C virus (HCV) accounts for 15%-20% of cases of acute infection, and chronic HCV infection is developed in about 50%-80% of HCV patients. Unfortunately, due to the lack of proper medical care, difficulty in screening for HCV infection, and lack of awareness resulted in chronic HCV infection in 71 million people on a global scale, and about 399,000 deaths in 2016. It is crucial to recognize that the effective use of antiviral medicines can cure more than 95% of HCV infected people. The Global Health Sector Strategy (GHSS) aim is to reduce the new HCV infections and the HCV associated mortality by 90% and 65%, respectively. Therefore, the methods that are simple, yet powerful enough to detect HCV infections with high sensitivity, specificity, and a shorter window period are crucial to restrain the global burden of HCV healthcare. This article focuses on the technologies used for the detection of HCV in clinical specimens.

Effect of Delonix regia (Boj. Ex Hook.) Raf. stem bark extract against experimentally induced ulcers in rats.

Delonix regia, commonly called Flame Tree or Flamboyant (locally, Gul Mohor) is a common tree traditionally used to treat various diseases like gastric problems, body pain, rheumatic pains of joints and wound healing. Here, we carried out biological profiling of Delonix regia as antiulcer agent. Antiulcer activity of the ethanol extract from stem bark was evaluated on pylorus ligation and indomethacin induced ulcer in Wistar albino rats. Ethanol extract from stem bark of D.regia was administered at the doses 100, 200 and 400 mg/kg/day, p.o. for 7 days. Ulcer index, gastric pH, volume, free acidity, total acidity, total carbohydrate (TC), protein (P), mucin content (TC/P) and gastric mucus were evaluated in pylorus ligation model, while ulcer index, malondialdehyde, GSH, PGE2, and gastric mucus were estimated in the indomethacin induced ulcer model. Ex vivo assay for the activity of H+/K+-ATPase was also done. The results showed significant inhibition on H+/K+-ATPase in a dose dependent manner and comparableto their respective positive control group of rats demonstrating that ethanol extract of stem bark of Delonix regia possesses significant antiulcer properties.

Protective effect of Dalbergia sissoo Roxb. ex DC. (family: Fabaceae) leaves against experimentally induced diarrhoea and peristalsis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dalbergia sissoo Roxb. ex DC. (family: Fabaceae; Indian Rosewood), is used in India, especially in rural communities by traditional medicine practitioners to treat diarrhoea. However, scientific evidence does not exist in any literature to substantiate the claim of therapeutic success of the plant species in diarrhoea. AIM: To study the protective effect of ethanol extract from D. sissoo Roxb. ex DC. leaves (EDSL) against experimentally induced diarrhoea and peristalsis in mice. MATERIALS AND METHODS: Castor oil-induced diarrhoea and magnesium sulphate (MgSO4)-induced diarrhoea tests were used to assess the antidiarrhoeal activity of D. sissoo. Gastrointestinal tract transit of charcoal meal test and barium sulphate milk was used to assess the peristalsis activity of the extract, while the acute toxicity study and determination of total phenolics and total flavonoids were carried out using well-established protocols and methods. RESULTS: The EDSL significantly reduced faecal output in castor oil-induced and MgSO4-induced diarrhoea and also significantly reduced the number of diarrhoeal episodes. D. sissoo significantly delayed the onset of diarrhoea induced by both castor oil and MgSO4 and comparable to loperamide, a standard antidiarrhoeal drug. Both D. sissoo and atropine sulphate significantly reduced the peristalsis activity of charcoal meal and barium sulphate milk in mice. The preliminary phytochemical analysis of EDSL revealed the presence of carbohydrates, phenolics, glycosides, and flavonoids. The median lethal dose of EDSL was greater than 2000 mg/kg (orally (p.o.)). CONCLUSION: The data obtained indicate that the EDSL has antidiarrhoeal and antiperistalsis activities and thus supports its traditional use. The data also show that the plant material given p.o. may be safe and/or non-toxic in mice.

Isolation of compound and CNS depressant activities of Mikania scandens Willd with special emphasis to brain biogenic amines in mice.

Mikania scandens, a twining herb that grows as a weed in India and Bangladesh is used as vegetables and is a good source of vitamin A, C, B complex, mikanin, sesquiterpenes, betasitosterin, stigmasterol and friedelin. The present communication reports CNS depressant activities with special emphasis to brain biogenic amines in mice. Ethanol extract of leaves of M. scandens (EEMS) was prepared by Soxhalation and analyzed chemically. EEMS potentiated sleeping time induced by pentobarbitone, diazepam and meprobamate and showed significant reduction in the number of writhes and stretches. EEMS caused significant protection against pentylene tetrazole-induced convulsion and increased catecholamines and brain amino acids level significantly. Results showed that EEMS produced good CNS depressant effects in mice.

Antidiabetic effect of Streblus asper in streptozotocin-induced diabetic rats.

CONTEXT: In the Indian traditional system of medicine, Streblus asper Lour (Moraceae) is prescribed for the treatment of diabetes mellitus. OBJECTIVE: In the present study, α-amyrin acetate isolated from S. asper, and the petroleum ether extract of S. asper stem bark (PESA) was screened for their antidiabetic properties in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Successive Soxhlet extraction of the dried stem bark with petroleum ether and then with ethanol (95%) yielded petroleum ether and ethanol extracts, respectively, which were concentrated under reduced pressure. Hyperglycemia was induced in rats by STZ (50 mg/kg, b.w.). Twenty-four hours after STZ induction, respective groups of diabetic rats received PESA (100, 250 and 500 mg/kg, b.w.) and α-amyrin acetate (25, 50 and 75 mg/kg, b.w.) respectively, orally daily for 15 days. Glibenclamide (0.5 mg/kg, orally) served as a reference. Blood glucose levels were measured on every 5th day during the 15 days of treatment. The serum lipid profiles and biochemical parameters, viz., serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), insulin and glycosylated hemoglobin level, were measured. RESULTS: PESA significantly (p < 0.01) normalized blood-glucose levels and serum biochemical parameters as compared with those of STZ controls. α-Amyrin acetate (75 mg/kg, b.w.) exhibited maximum glucose lowering effect (71.10%) in diabetic rats compared to the other dose (25, 50 mg/kg) at the end of the study. The protective effect was further confirmed by histopathological examination of the liver. CONCLUSION: PESA and α-amyrin acetate demonstrated remarkable antidiabetic activity in STZ-induced diabetic rats.

Tropolones and Thailandepsin B as Lead-like Natural Compounds in the Development of Potent and Selective Histone Deacetylase Inhibitors.

BACKGROUND: Tropolone and thailandepsin B are naturally occurring substances that are primarily isolated from fungi and plants, although they can also be found in certain bacteria. Tropolones belong to an important class of aromatic compounds with a seven-membered nonbenzenoid ring structure. Thailandepsins are a group of natural products that were initially discovered in the culture broth of the Gram-negative bacterium Burkholderia thailandensis. Tropolonebased structures have been identified in over 200 natural compounds, ranging from simple tropolone derivatives to complex multicyclic systems like pycnidione and pyrerubrine A. These natural compounds exhibit a diverse range of pharmacological effects, including antibacterial, antifungal, insecticidal, phytotoxic, anti-inflammatory, antimitotic, anti-diabetic, enzyme inhibitory, anticancer, cytoprotective, and ROS scavenging properties. It is worth noting that thujaplicane, a compound similar to tropolone, displays all of the listed biological activities except for antimitotic action, which has only been observed in one natural tropolone compound, colchicine. Tropolone can be synthesized from commercially available seven-membered rings or derived through various cyclization and cycloaddition reactions. Thailandepsin B, on the other hand, can be synthesized by macro-lactonization of the corresponding secoacid, followed by the formation of internal disulfide bonds. It is important to mention that thailandepsin B exhibits different selective inhibition profiles compared to FK228. OBJECTIVE: We investigated the HDAC inhibitory activity of the Tropolones and Thailandepsin B and discussed the biosynthesis of the naturally occurring compounds and their synthetic scheme. RESULTS AND CONCLUSION: It has been observed that Tropolone derivatives act as isoenzyme-selective inhibitors of proven anticancer drug targets, histone deacetylases (HDACs). Some monosubstituted tropolones show remarkable levels of selectivity for HDAC2 and strongly inhibit the growth of T-lymphocyte cell lines. And Thailandepsins have different selective inhibition profiles than FK228. They exhibit comparable inhibitory activities to FK228 against human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9, but less potent inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which may be useful. Thailandepsins possess potent cytotoxic activities toward some types of cell lines.

Histone Deacetylase Inhibitors as Cognitive Enhancers and Modifiers of Mood and Behavior.

BACKGROUND: Epigenetic regulation of gene signalling is one of the fundamental molecular mechanisms for the generation and maintenance of cellular memory. Histone acetylation is a common epigenetic mechanism associated with increased gene transcription in the central nervous system (CNS). Stimulation of gene transcription by histone acetylation is important for the development of CNS-based long-term memory. Histone acetylation is a target for cognitive enhancement via the application of histone deacetylase (HDAC) inhibitors. The promising potential of HDAC inhibitors has been observed in the treatment of several neurodevelopmental and neurodegenerative diseases. OBJECTIVE: This study assessed the current state of HDAC inhibition as an approach to cognitive enhancement and treatment of neurodegenerative diseases. Our analysis provides insights into the mechanism of action of HDAC inhibitors, associated epigenetic priming, and describes the therapeutic success and potential complications after unsupervised use of the inhibitors. RESULTS AND CONCLUSION: Several chromatin-modifying enzymes play key roles in the regulation of cognitive processes. The importance of HDAC signaling in the brain is highlighted in this review. Recent advancements in the field of cognitive epigenetics are supported by the successful development of various HDAC inhibitors, demonstrating effective treatment of mood-associated disorders. The current review discusses the therapeutic potential of HDAC inhibition and observed complications after mood and cognitive enhancement therapies.

Potential of Synthetic and Natural Compounds as Novel Histone Deacetylase Inhibitors for the Treatment of Hematological Malignancies.

Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that remove or add acetyl groups to lysine residues of histones, respectively. Histone deacetylation causes DNA to more snugly encircle histones and decreases gene expression, whereas acetylation has the opposite effect. Through these small alterations in chemical structure, HATs and HDACs regulate DNA expression. Recent research indicates histone deacetylase inhibitors (HDACis) may be used to treat malignancies, including leukemia, B-cell lymphoma, virus-associated tumors, and multiple myeloma. These data suggest that HDACis may boost the production of immune-related molecules, resulting in the growth of CD8-positive T-cells and the recognition of nonreactive tumor cells by the immune system, thereby diminishing tumor immunity. The argument for employing epigenetic drugs in the treatment of acute myeloid leukemia (AML) patients is supported by evidence that both epigenetic changes and mutations in the epigenetic machinery contribute to AML etiology. Although hypomethylating drugs have been licensed for use in AML, additional epigenetic inhibitors, such as HDACis, are now being tested in humans. Preclinical studies evaluating the efficacy of HDACis against AML have shown the ability of specific agents, such as anobinostat, vorinostat, and tricostatin A, to induce growth arrest, apoptosis, autophagy and cell death. However, these inhibitors do not seem to be successful as monotherapies, but instead achieve results when used in conjunction with other medications. In this article, we discuss the mounting evidence that HDACis promote extensive histone acetylation, as well as substantial increases in reactive oxygen species and DNA damage in hematological malignant cells. We also evaluate the potential of various natural product-based HDACis as therapeutic agents to combat hematological malignancies.

Fractionation of stigmasterol derivative and study of the effects of Celsia coromandelina aerial parts petroleum ether extract on appearance of puberty and ovarian steroidogenesis in immature mice.

CONTEXT: Celsia coromandelina Vahl (Scrophulariaceae) is a shrub found throughout Bangladesh and India, and it is distributed widely in the plains of West Bengal. It is used by the tribal people to treat diarrhea, dysentery, insomnia, skin eruption, fever, syphilis, helminthes infection, and to control fertility. OBJECTIVE: The objective of this study was to fractionate stigmasterol derivative and to investigate the effects of petroleum ether extract of C. coromandelina (PECC) aerial parts on the onset of reproductive maturity and the ovarian steroidogenesis in immature female mice. MATERIALS AND METHODS: PECC was prepared by hot extraction process and one compound was isolated by preparative TLC from it. PECC was completely freed from solvent and administered in immature female mice intraperitoneally once on every alternate day for nine doses. The sexual maturity was observed by means of vaginal opening, first estrus (days), rate of body growth, changes in weight of ovary, uterus and pituitary. The content of ascorbic acid, cholesterol, Δ5-3ß-hydroxy steroid dehydrogenase (Δ5-3ß-HSD) and glucose 6-phosphate dehydrogenase (G 6-PDH) activities in ovaries and carbonic anhydrase activity in uterus were measured by means of biochemical technique in control and treated mice. The activity of PECC was compared with standard marker compound ethinyl estradiol. RESULTS: The isolated compound was characterized as stigmasterol derivative. PECC treatment caused a remarkable delay (30.27 and 18.56%, respectively, by low dose) in sexual maturity compared to vehicle control as evidenced by the age of vaginal opening and appearance of first estrus (cornified smear). PECC treatment also caused a significant fall (58.6 and 50.0%, respectively, by low dose) in Δ5-3ß-HSD and G 6-PDH activities involved in ovarian steroidogenesis compared to vehicle control. Total cholesterol and ascorbic acid content in ovaries and carbonic anhydrase activity in uterus were increased significantly (low dose by 49.3, 424.6 and 82.4%, respectively) along with a reduction in the weight of ovary, uterus and pituitary in comparison to that of control. DISCUSSION AND CONCLUSION: Overall, these results demonstrate that PECC has a good antifertility effect and is responsible for the delayed development of sexual maturity, suppression of ovarian steroidogenesis and elevation of carbonic anhydrase activity in uterus of immature mice. This supports the claim by tribal people as a potential remedy for birth control.

Hypoglycaemic effect of Melothria heterophylla in streptozotocin-induced diabetic rats.

CONTEXT: In the Indian traditional system of medicine, Melothria heterophylla (Lour.) Cogn., (Cucurbitaceae) is prescribed for the treatment of diabetes mellitus. OBJECTIVE: In the present study, the antidiabetic effect of ethanol extract of Melothria heterophylla (EEMH), and its active isolated constituents were investigated in streptozotocin (STZ)-induced diabetic Swiss albino rats. METHOD: Successive Soxhlet extraction of the dried total aerial parts with petroleum ether for defatting and then with ethanol (95%) to obtain ethanol extract, which was concentrated under reduced pressure. Hyperglycemia was induced in rats by STZ (50 mg/kg, body weight). Twenty-four hours after STZ induction, respective groups of diabetic rats received EEMH (200 and 400 mg/kg, body weight), gallic acid (GA) (2 and 4 mg/kg, body weight), and rutin (RU) (2 and 4 mg/kg, body weight), respectively, orally daily for 15 days. Glibenclamide (0.5 mg/kg, orally) served as reference. Blood glucose levels and change in body weight were measured on every 5(th) day during 15 days of treatment. Biochemical parameters, viz., serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and serum insulin, were measured. RESULTS: EEMH and its active constituents significantly (p < 0.01) normalized blood glucose levels and serum biochemical parameters as compared to those of STZ controls. Both GA (4 mg/kg) and RU (4 mg/kg) exhibited maximum glucose lowering effect (69.1 and 66.7%, respectively) in diabetic rats compared to the other dose (2 mg/kg) at the end of the study. EEMH, gallic acid and RU also showed significant increase in serum insulin, and body weight of STZ-induced diabetic rats. CONCLUSION: Therefore, ethanol extract of Melothria heterophylla, GA and RU demonstrated remarkable antidiabetic activity in STZ-induced diabetic rats.

Terpenoids of methanol extract of Clerodendrum infortunatum exhibit anticancer activity against Ehrlich's ascites carcinoma (EAC) in mice.

CONTEXT: Clerodendrum infortunatum Linn. is a widely used plant in the Indian indigenous system of medicine for the treatment of tumors. OBJECTIVE: The present study evaluated the anticancer activity of methanol extract of C. infortunatum (MECI) against Ehrlich's ascites carcinoma (EAC) bearing Swiss albino mice and isolation of bioactive terpenoids from it. METHODS: HPLC analysis of the methanol extract showed the presence of three major components. Out of those, two compounds were isolated and characterized as oleanolic acid and clerodinin A. The anticancer activity of MECI was assessed by measuring the tumor growth response, percentage increase of life span, study of hematological parameters, lipid peroxidation, antioxidant enzyme activity like glutathion and CAT. In vitro cytotoxicity assay was also performed using EAC cell lines. RESULT AND CONCLUSION: Treatment with MECI causes significant decrease in the tumor cell volume and increase in the life span. The median survival time (MST) of EAC control group was found as 19.42 ± 0.91 d, whereas the MST was increased to 23.44 ± 2.69 d and 27.57 ± 2.57 d for the groups treated with MECI at 100 and 200 mg/kg, respectively. All the hematological parameters, malonaldehyde content and antioxidant enzymes' activity were restored towards the normal level. IC(50) value of MECI was found as 498.33 µg/mL in cytotoxicity study. The experimental results suggested that MECI has significant anticancer activity, which can be attributed to the presence of oleanolic acid and clerodinin A.

Importance of Indazole against Neurological Disorders.

Indazole is a nitrogen-containing bicyclic compound, having three tautomeric forms: 1Hindazole, 2H-indazole, and 3H-indazole. Mostly, they are considered as 1H-indazole tautomeric forms, although they have the potential to tautomerism to 2H- and 3H-indazole forms. Indazoles are involved in a wide variety of biological and enzymatic processes. Therefore, they exhibit a series of pharmacological activities. Indazoles show potent activities against neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), mood disorders, etc., by inhibiting different signaling pathways and the generation of neurotransmitters and activation of enzyme activity. They effectively prevent neurological diseases by different mechanisms, such as by inhibiting the monoamine oxidase (MAO) and kinase enzymes like Glycogen synthase kinase 3 (GSK3), and leucinerich repeat kinase enzyme 2 (LRRK2). In this article, we have discussed multiple causative strategies of indazole to treat neurological diseases. This has aroused special attention in the discovery of the novel indazoles and their biological activities.

Indazole Derivatives Effective against Gastrointestinal Diseases.

BACKGROUND: In this fast-growing lifestyle, humans are in the race against time to cope up with busy schedule. Less exercise, consumption of high calorie-low fiber food and stress take us one step closer towards digestive dysfunction. Dysfunctional digestive system causes various gastrointestinal disorders like constipation, IBS, UC, diarrhea, gastrointestinal tract immobility, hyperglycemia, hemorrhoids, fistula, anal fissures, stomach cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer and metabolic syndrome. Amongst various natural and synthetic indazole derivatives nigellicine, nigellamine, nigellidine, zanubrutinib and SCH772984 showed prominent results to cure various gastrointestinal disorders. OBJECTIVES: In this manuscript, we focus on the importance of indazole derivatives in the treatment of various gastrointestinal diseases. RESULTS AND CONCLUSION: In the treatment of IBS, four positions (R1, R2, R3 and R4) of indazole were mainly substituted with aromatic aldehyde/substituted methyl, aromatic acid/formamide, benzamide/ sulfonamide and methyl groups, respectively. In case of diarrhea and metabolic syndrome treatment, substitutions with benzyl/isopropyl/acetaldehyde (R1 position) and carboxamide/ formamide (R2 position) of indazole play a critical role. Also, in the treatment of diabetes melitus, all six positions of indazole derivative were substituted with substituted aryl/alkyl/aromatic acid, substituted formamide, substituted acetamide/hydrazide group, halo aryl, substituted aryl/aromatic acid and a long chain of alkyl-aryl alcohol groups, respectively. In the treatment of gastrointestinal cancers, all six positions of indazole derivative were substituted with benzylamide (R1), octanediamide/ benzamide/formamide (R2), carbaldehyde (R4) and substituted phenyl (R5 and R6) groups, respectively. Six receptors (6NP0, 2YME, 4EFU, 4WZ8, 5U4W and 7KKP) associated with GI disorders (co-crystallized with indazole derivative) were identified. Analysis of the receptors showed that co-crystalized ligand molecules were well-interacted with receptors via pie-pie interaction, coordinate and sigma bonding within 4 Å distance. As per Ramachandran plot analysis, more than 90% of the amino acid residues were present in the most favored region. So, if sufficient focuses are imposed on the development of newer indazole derivatives to treat gastrointestinal diseases, it will work as a boon to society.

Combination Therapy of Ledipasvir and Itraconazole in the Treatment of COVID-19 Patients Coinfected with Black Fungus: An In Silico Statement.

The manuscript mainly aimed at providing clues on improving the innate immunity of coronavirus patients and safeguarding them from both new mutant strains and black fungus infections. Coronavirus is readily mutating from one variant to another. Among the several variants, we selected SARS-CoV-2 B.1.1.7 in this study. Upon infection of any virus, ideally, the phagocytic cells of the host engulf and destroy the virus by a mechanism called phagocytosis. However, compromised immunity impairs phagocytosis, and thus, restoring the immune system is crucial for a speedy recovery of infected patients. The autophagy and activation of Toll-like receptor-4 are the only ways to restore innate immunity. Recently, immunocompromised COVID-19 patients have been suffering from the coinfection of black fungus. Rhizomucor, a black fungus species, causes more than 75% of cases of mucormycosis. Here, we present the results of molecular docking studies of sixty approved antiviral drugs targeting receptors associated with the SARS-CoV-2 B 1.1.7 variant (PDB id: 7NEH), activating the innate immune system (PDB id: 5YEC and 5IJC). We also studied the twenty approved antifungal drugs with Rhizomucor miehei lipase propeptide (PDB id: 6QPR) to identify the possible combination therapy for patients coinfected with coronavirus and black fungus. The ledipasvir showed excellent docking interactions with the 7NEH, 5YEC, and 5IJC, indicating that it is a perfect candidate for the treatment of COVID-19 patients. Itraconazole showed significant interaction with 6QPR of Rhizomucor miehei, suggesting that itraconazole can treat black fungus infections. In conclusion, the combination therapy of ledipasvir and itraconazole can be a better alternative for treating COVID-19 patients coinfected with black fungus.

Gossypol and Its Natural Derivatives: Multitargeted Phytochemicals as Potential Drug Candidates for Oncologic Diseases.

Despite the vast amounts of research and remarkable discoveries that have been made in recent decades, cancer remains a leading cause of death and a major public health concern worldwide. Gossypol, a natural polyphenolic compound derived from the seeds, roots, and stems of cotton (Gossypium hirsutum L.), was first used as a male contraceptive agent. Due to its diverse biological properties, including antifertility, antiviral, antioxidant, antibacterial, antimalarial, and most notably antitumor activities, gossypol has been the subject of numerous studies. Nevertheless, no systematic review has been performed that analyzes the antineoplastic potential of gossypol and related natural compounds in an organ-specific manner while delineating the molecular mechanisms of action. Hence, we have performed an extensive literature search for anticancer properties of gossypol and their natural derivatives against various types of cancer cells utilizing PubMed, ScienceDirect, Google Scholar, and Scopus. The sources, distribution, chemical structure, and toxicity of gossypol and its constituents are briefly reviewed. Based on emerging evidence, gossypol and related compounds exhibit significant antineoplastic effects against various cancer types through the modulation of different cancer hallmarks and signaling pathways. Additionally, the synergistic activity of gossypol and its derivatives with chemotherapeutic agents has been observed. Our evaluation of the current literature suggests the potential of gossypol and its derivatives as multitargeting drug candidates to combat multiple human malignancies.

Development, optimization, and anti-diabetic activity of gliclazide-loaded alginate-methyl cellulose mucoadhesive microcapsules.

The purpose of this work was to develop and optimize gliclazide-loaded alginate-methyl cellulose mucoadhesive microcapsules by ionotropic gelation using central composite design. The effect of formulation parameters like polymer blend ratio and cross-linker (CaCl(2)) concentration on properties of gliclazide-loaded alginate-methyl cellulose microcapsules like drug encapsulation efficiency and drug release were optimized. The optimized microcapsules were subjected to swelling, mucoadhesive, and in vivo studies. The observed responses coincided well with the predicted values from the optimization technique. The optimized microcapsules showed high drug encapsulation efficiency (83.57 ± 2.59% to 85.52 ± 3.07%) with low T(50%) (time for 50% drug release, 5.68 ± 0.09 to 5.83 ± 0.11 h). The in vitro drug release pattern from optimized microcapsules was found to be controlled-release pattern (zero order) with case II transport release mechanism. Particle sizes of these optimized microcapsules were 0.767 ± 0.085 to 0.937 ± 0.086 mm. These microcapsules also exhibited good mucoadhesive properties. The in vivo studies on alloxan-induced diabetic rats indicated the significant hypoglycemic effect that was observed 12 h after oral administration of optimized mucoadhesive microcapsules. The developed and optimized alginate-methyl cellulose microcapsules are suitable for prolonged systemic absorption of gliclazide to maintain lower blood glucose level and improved patient compliance.

CNS activities of ethanol extract of aerial parts of Hygrophila difformis in mice.

The ethanol extract of aerial parts of Hygrophila difformis (EEHD) was tested for possible pharmacological effects on experimental animals. EEHD significantly potentiated the sleeping time of mice induced by standard hypnotics, viz. pentobarbital sodium, diazepam, and meprobamate in a dose dependent manner. EEHD showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. Pretreatment with EEHD caused significant protection against strychnine and leptazol-induced convulsions. The behavioral studies on mice indicate CNS depressant activity of the ethanol extract of H. difformis.