Novel designed analogues of quercetin against SARS-CoV2:an in-silico pharmacokinetic evaluation, molecular modeling, MD simulations based study.

Here we present the design of the series of quercetin analogues and their molecular docking study involving the binding of quercetin and its analogues with SARS-CoV2 3CLpro. The scientific literature shows that quercetin compound has been successfully used against SARS-CoV by inhibiting the replication of virus in respiratory epithelial cell through the inhibition of the SARS-CoV main protease (3CLpro.) It was suggested that the modification at position 3 in quercetin structure may produce potent compounds against SARS-CoV2. A series of quercetin analogues were designed and screened for physicochemical and pharmacokinetics parameters. The activities of selected compounds against SARS-CoV2 were screened by molecular modelling and evaluated that analogues, Q5, Q6 and Q13 have the best docking scores (-8.01 to -8.17 kcal/mol) and also better than quercetin, α-ketoamide and current available inhibitors of the same target. The structure-activity relationship (SAR) study revealed that the introduction of the amino group in a designed molecule was highly promising for increasing the inhibitory activity against SARS-CoV2 3CL pro. Moreover, to check the stability and orientation of selected compounds inside the binding pocket, the molecular dynamic simulations were performed for 100 ns. Results revealed that the designed analogues Q1, Q6 and Q13 having lowest binding energies (-8.0, -8.17 and -8.06 kcal/mol respectively) as well as better physicochemical properties, pharmacokinetics, and toxicity profile show their potential to synthesize and develop as the therapeutic agents against corona virus.Communicated by Ramaswamy H. Sarma.

Highly potent anti-inflammatory, analgesic and antioxidant activities of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones.

Four series of tetrahydro-2H-1,3,5-thiadiazine-2-thiones (series A and B including two novel enantiopure isomers), tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series C) and N-3 ester derivatives of tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series D) were synthesized and evaluated for their anti-inflammatory, analgesic and anti-oxidant activities. These THTT analogues specially series D were first time examined for their in vitro anti-inflammatory, in vivo analgesic and anti-oxidant activities. Among them lipophilic compounds (series B and D) were found to be highly active for anti-inflammatory evaluation with IC50 values between 5.1-16.9 and 4.1-32.4 µM, respectively when compared with the standard drug ibuprofen IC50 = 11.2 µM. The structure-activity relationship exposed the importance of lipophilic substituents especially ester and n-propyl group for inhibition of inflammation. The molecular docking studies demonstrated that all the active analogues of THTT have notable binding relations with Arg120 of the active sites of COX-1 enzyme either through CS moiety of the THTT nucleus or with COO attached at N-3 of THTT nucleus. In vivo analgesic activity of the selected THTT compounds 14, 17, 18, 19 (series B) and 28 (series D) were also carried out by acetic acid-induced writhing procedure. The compound 28 showed significant anti-nociceptive/analgesic activity at the oral dose of 5 mg/kg body weight with the percent protection (32.05 %) when compared with standard indomethacin at 10 mg/kg (48.83 %). Additionally, these compounds demonstrated the moderate level of antioxidant potential with IC50 values in the range of 60.9 to 93.6 µM (standard butylated hyroxyanisole; IC50 = 44.2 µM). These results indicated that this class of heterocyclic compounds may be a template specially to design better anti-inflammatory and analgesic agents.

Xanthones: A Class of Heterocyclic Compounds with Anticancer Potential.

Xanthones (9H xanthen-9-one) are an important class of heterocyclic compounds containing oxygen and a moiety of gamma-pirone, dense with a two-benzene ring structure, distributed widely in nature. Naturally occurring xanthones are found in micro-organisms and higher plants as secondary metabolites in fungi and lichens. Compounds of the family Caryophyllaceae, Guttiferae and Gentianaceae, are the most common natural source of xanthones. The structure of the xanthones nucleus, coupled with its biogenetic source, imposes that the carbons are numbered according to the biosynthetic pact. The characteristics oxygenation pattern of xanthones earlier is mixed shikimateacetate biogenesis. The major class of xanthones includes simple oxygenated, non-oxygenated, xanthonolignoids, bisxanthones, prenylated and related xanthones, miscellaneous xanthones. Their great pharmacological importance and interesting scaffolds were highly encouraged by scientists to investigate either the synthesis design or natural products for cancer treatment. Because currently used antitumor drugs possess high toxicity and low selectivity, efficacious treatment may be compromised. This review is limited to the antitumor activity of xanthones and the chemistry of xanthone core, which may help provide fundamental knowledge to the medicinal chemist for new and advanced research in drug development.

Gemifloxacin-transition metal complexes as therapeutic candidates: antimicrobial, antifungal, anti-enzymatic, and docking studies of newly synthesized complexes.

In the era of acquired microbial resistance (AMR), resulting in the ineffectiveness of antibiotics is of keen interest for researchers in current scenarios. Ten novel metal complexes of gemifloxacin have been synthesized by reacting it with essential and trace elements in a 2:1 ratio predetermined conducto-metrically. As these metals are either present in the body or co-administered as metallic supplements can alter the level of antibiotics. Therefore, Metal complexes of Gemifloxacin, an important member of the fluoroquinolone family, were synthesized. The possible coordination of gemifloxacin with these metals has been proposed by the electronic and elemental data obtained through molar conductance, elemental analysis, and spectroscopic techniques like ultraviolet-visible (UV-Vis), infrared (IR), and proton-nuclear magnetic resonance (1H NMR) studies. In the light of these studies, the monoanionic bidentate ligand behavior of gemifloxacin in complexation with metals has been revealed. For in-vitro microbial studies, these newly synthesized complexes were tested against eleven different bacteria including Gram + ve and Gram -ve organisms, and one fungal strain. The results were compared with the parent drug by applying ANOVA through SPSS software version 22. Therefore, it has been found that among all synthesized metal complexes, the G-M01 complex exhibits increased activity against B. subtilis, P. mirabilis, E. coli, K. pneumonia, and C. freundii. Complex G-M02, G-M03, G-M04, and G-M10 show more pronounced activity than Gemifloxacin against S. aureus and M. luteus. Moreover, the binding orientations of the synthesized metal complexes into the binding site of the urease enzyme revealed that all the docked metal complexes oriented away from the Ni bi-center, and the inactivation of urease is due to their interaction with entrance flap residues.

Potent In Vitro Phosphodiesterase 1 Inhibition of Flavone Isolated from Pistacia integerrima Galls.

To prospect an isozyme-specific, effective inhibitor against the physiologically-crucial enzyme phosphodiesterase 1 (PDE1), phytochemicals from Pistacia integerrima galls were screened. The chloroform fraction of gall extract was subjected to column chromatographic which led to the isolation of compound 1, elucidated to be 5-hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (a flavone). In vitro and in silico PDE1 inhibitory activity of the compound 1 was investigated. EDTA, a known PDE1 inhibitor, was used as the reference. The flavone exhibited in vitro attenuation towards snake venom PDE1. IC50 response was superior to the standard chelator. An in silico molecular docking study was carried out using 3D structure of PDE1 to study the binding interactions of compound 1. The docking study predicted that flavone had a lower binding affinity (-7.6 kcal/mol) and total energy (-95 kcal/mol) score compared to EDTA. The minimal energy associated with the ligand-protein complex implied that isolated compound 1 can serve as a therapeutic agent against PDE1 enzyme-provoked ailments like asthma, hypertension, schizophrenia, and erectile dysfunction.

Simultaneous determination of moxifloxacin with NSAIDs in API, dosage and serum by reverse phase high-performance liquid chromatography: Application to in vitro drug interactions.

Experimental design is a significant tool for optimization and validation for the development of HPLC methods to determine API in both human serum and pharmaceutical formulations. In this study, RP-HPLC method is developed and validated for the simultaneous determination of moxifloxacin and NSAIDs. In this experiment, Purospher STAR C18 column with optimum assay conditions (10:90, v/v, water: methanol, pH 2.75) used as mobile phase having flow rate of 1.5mL min-1 and screened at 240 nm. The experimental results exhibit reliability through accuracy (98-102%), precision (0.011-1.85%) and linearity (R2>0.999) in range of 0.15-40µgmL-1. The LOD and LOQ limits for moxifloxacin and NSAIDs are found to be 0.015 and 0.046 µgmL-1 respectively. The significant outcomes conclude that the developed method for assay is effectively suitable to human serum and pharmaceutical formulations and there is no interference from excipients of tablets and serum. The proposed method is useful for drug-interaction and investigation of moxifloxacin with NSAIDs.

Report: Metformin potential in predisposing arthralgia, type II cross reactivity secondary to group A streptococcus infection & other comorbidities in treating PCOS.

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.

A novel HPTLC method for quantitative estimation of biomarkers in polyherbal formulation

Objective:To explore the quantitative estimation of biomarkers gallic acid and berberine in polyherbal formulation Entoban syrup. Methods: High performance thin layer chromatography was performed to evaluate the presence of gallic acid and berberine employing toluene:ethyl acetate:formic acid:methanol 12:9:4:0.5 (v/v/v/v) and ethanol: water: formic acid 90:9:1 (v/v/v), as a mobile phase respectively. Results:The Rf values (0.58) for gallic acid and (0.76) for berberine in both sample and reference standard were found comparable under UV light at 273 nm and 366 nm respectively. The high performance thin layer chromatography method developed for quantization was simple, accurate and specific. Conclusions: The present standardization provides specific and accurate tool to develop qualifications for identity, transparency and reproducibility of biomarkers in Entoban syrup.