Role of novel sodium glucose co-transporter-2 inhibitor enavogliflozin in type-2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Enavogliflozin is a novel sodium glucose co-transporter-2 inhibitor (SGLT2i) developed in South Korea. This meta-analysis was done as no meta-analysis has analysed the efficacy and safety of enavogliflozin in type-2 diabetes (T2DM). METHODS: Electronic databases were systematically reviewed for randomized controlled trials having patients with T2DM receiving enavogliflozin in treatment-arm, and placebo/any other medicine in control-arm. Primary outcome was to evaluate changes in glycosylated haemoglobin (HbA1C). Secondary outcomes were to evaluate alterations in fasting glucose (FPG), 2-h post prandial glucose (2-h PPG), blood pressure (BP), weight, lipids, and adverse events. RESULTS: Data from 4 trials (684 patients) was analysed for clinical outcomes over 12-24 weeks clinical use. Compared to placebo, patients receiving enavogliflozin had significantly lower HbA1c [MD -0.76%(95% CI: 0.93 to -0.60); P < 0.00001; I2 = 97%], FPG [MD -2.12 mmol/l(95%CI: 2.47 to -1.77); P < 0.00001; I2 = 91%], body-weight [MD-1.37 kgs (95% CI: 1.73-1.00); P < 0.00001; I2 = 89%], systolic BP [MD-4.99 mm Hg (95%CI: 7.83 to -2.16); P = 0.0006; I2 = 47%], diastolic BP [MD-3.09 mm Hg(95%CI: 3.38 to -2.81); P < 0.00001; I2 = 0%]. Treatment emergent adverse-events [OR1.16(95%CI:0.64-2.09); P = 0.63; I2 = 0%], serious adverse events [OR1.81(95%CI:0.37-8.83); P = 0.46; I2 = 0%], urinary infections [OR1.37(95%CI:0.09-20.61); P = 0.82; I2 = 33%] and genital infections [OR 3.07(95%CI:0.31-29.88); P = 0.33; I2 = 0%] were comparable. Compared to dapagliflozin, patients receiving enavogliflozin had significantly lower HbA1c [MD-0.06%(95%CI: 0.07-0.05); P < 0.00001; I2 = 0%], FPG [MD-0.19 mmol/l(95%CI: 0.21 to -0.17); P < 0.00001; I2 = 0%], body-weight [MD-0.20 kgs(95%CI: 0.24 to -0.15); P < 0.00001; I2 = 0%], diastolic BP [MD -0.92 mm Hg (95%CI: 1.36 to -0.48); P < 0.0001; I2 = 91%] and significantly higher urine glucose creatinine ratio [MD 16.69 g/g (95%CI:16.11-17.26); P < 0.00001; I2 = 0%]. CONCLUSION: Enavogliflozin is a well tolerated and effective SGLT2i for T2DM and may be superior to dapagliflozin with regard to certain clinical aspects over 6 months clinical use.

Synthesis, molecular docking, antimycobacterial and antimicrobial evaluation of new pyrrolo[3,2-c]pyridine Mannich bases.

In this report, we describe the synthesis and biological evaluation of a new series of pyrrolo[3,2-c]pyridine Mannich bases (7a-v). The Mannich bases were obtained in good yields by one-pot three component condensation of pyrrolo[3,2-c]pyridine scaffold (6a-c) with secondary amines and excess of formaldehyde solution in AcOH. The chemical structures of the compounds were characterized by 1H NMR, 13C NMR, LC/MS and elemental analysis. Single crystal X-ray diffraction has been recorded for compound 7k ([C23H29ClN4]+2, H2O). The in vitro antimicrobial activities of the compounds were evaluated against various bacterial and fungal strains using Agar diffusion method and Broth micro dilution method. Compounds 7e, 7f, 7r, 7t, and 7u were showed good Gram-positive antibacterial activity against S. aureus, B. flexus, C. sporogenes and S. mutans. Furthermore, in vitro antimycobacterial activity was evaluated against Mycobacterium tuberculosis H37Rv (ATCC 27294) using MABA. Compounds 7r, 7t, and 7u were showed good antitubercular activity against Mtb (MIC ≥6.25 µg/mL). Among the tested compounds, 1-((4-chloro-2-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)piperidine-3-carboxamide (7t) was showed excellent antimycobacterial activity against Mtb (MIC <0.78 µg/mL) and low cytotoxicity against the HEK-293T cell line (SI >>25). Molecular docking of the active compounds against glutamate racemase (MurI) and Mtb glutamine synthetase were explained the structure-activity observed in vitro.

New polyfunctional imidazo[4,5-C]pyridine motifs: synthesis, crystal studies, docking studies and antimicrobial evaluation.

New antimicrobial agents, imidazo[4,5-c]pyridine derivatives have been synthesized. We have developed a new synthetic protocol for the final reaction, an efficient microwave-assisted synthesis of imidazo[4,5-c]pyridines from substituted 3,4-diaminopyridine and carboxylic acids in presence of DBU mediated by T3P. The chemical structures of the new compounds were characterized by IR, (1)H NMR, (13)C NMR, mass spectral analysis and elemental analysis. In addition, single crystal X-ray diffraction has also been recorded for compound 9c. The in vitro antimicrobial activities of the compounds were conducted against various Gram-negative, Gram-positive bacteria and fungi. Amongst the tested compounds 9c, 9e, 9g, 9k and 9l displayed promising antimicrobial activity. The molecular docking of GlcN-6-P synthase with newly synthesized compounds was carried out.

Wound healing and protease inhibition activity of Bacoside-A, isolated from Bacopa monnieri wettest.

Bacopa monnieri (L.) Wettest. (Scrophulariaceae) is a well-known medicinal herb. In the Indian system of medicine it is known as Brahmi (Sanskrit) and Indian water hyssop. Methanolic extract of Bacopa monnieri and its isolated constituent Bacoside-A were screened for wound healing activity. Bacoside-A was screened for wound healing activity by excision, incision and dead space wound on Swiss albino rats. Significant wound healing activity was observed in both extract and the Bacoside-A treated groups. The SDS-PAGE caseinolytic zymogram analysis of inhibition of matrix metalloproteases (MMPs) enzyme from the excision wound by Bacoside-A, an isolated constituent, was done with the concentrations 100 and 200 micromg/ml. In Bacoside-A treated groups, epithelialization of the excision wound was faster with a high rate (18.30 +/- 0.01 days) of wound contraction. The tensile strength of the incision wound was increased (538.47 +/- 0.14 g) in the Bacoside-A treated group. In the dead space wound model, the weight of the granuloma was also increased (89.15 +/- 0.08 g). The histological examination of the granuloma tissue of the Bacoside-A treated group showed increased cross-linking of collagen fibers and absence of monocytes. The wound healing activity of Bacoside-A was more effective in various wound models compared to the standard skin ointment Nitrofurazone.

Synthesis, DNA binding, docking and photoclevage studies of novel benzo[b][1,8]naphthyridines.

The synthesis and docking studies of novel benzo[b][1,8]naphthyridines is discribed. The docking studies show that the derivatives prefer to bind the AT-rich region of double stranded DNA (ds-DNA). The maximum binding energy -7.16 (kcal/mol) was observed for benzo[b][1,8]naphthyridine-5-thiol 5a and it is a better candidate as an enantioselective binder to ds-DNA than the other derivatives of benzo[b][1,8]naphthyridines. When photoirradiated at 365 nm, benzo[1,8]-naphthyridines have been found to promote the photocleavage of plasmid pUC19 DNA.

Wound healing activity and docking of glycogen-synthase-kinase-3-beta-protein with isolated triterpenoid lupeol in rats.

A triterpene compound lupeol isolated from petroleum ether extract of leaves of Celastrus paniculatus was screened for wound healing activity (8 mg/ml of 0.2% sodium alginate gel) by excision, incision and dead space wound models on Swiss Albino rats (175-225 g). In lupeol treated groups wound healing activity was more significant (17.83+/-0.48) than the standard skin ointment nitrofurazone (18.33+/-0.42). Epithelialization of the incision wound was faster with a high rate of wound contraction (571.50+/-5.07) as compared with the control group. In dead space wound model also the weight of the granulation tissue of the lupeol treated animal was increased indicating increase of collagenation and absence of monocytes. The comparative docking of isolated lupeol molecule and standard drug nitrofurazone to glycogen synthase kinase 3-beta protein by Wnt signaling pathway also supported the wound healing property of lupeol. The activation domain of GSK3-beta consisted of Tyr216, with residues Asn64, Gly65, Ser66, Phe67, Gly68, Val70, Lys85, Leu132, Val135, Asp181 in the active pocket docked with lupeol at the torsional degree of freedom 0.5 units with Lamarckian genetic algorithm showed the inhibition constant of 1.38 x 10(-7). The inhibition constant of nitrofurazone was only 1.35 x 10(-4).

Wound healing activity of embelin isolated from the ethanol extract of leaves of Embelia ribes Burm.

Ethanol extract of the leaves of Embelia ribes Burm. (Myrsinaceae) and its isolated quinone compound embelin were screened for wound healing activity by excision, incision and dead space wound models on Swiss Albino Rats. Significant wound healing activity was observed in both ethanol crude extract (30 mg/ml) and the constituent treated groups. In embelin treated groups (4 mg/ml of 0.2% sodium alginate gel), epithelialization of the incision wound was faster with a high rate of wound contraction. The tensile strength of the incision wound was significantly increased than the ethanol extract. In dead space wound model also the weight of the granulation was increased indicating increase in collagenation. The histological examination of the granulation tissue of embelin treated group showed increased cross-linking of collagen fibers and absence of monocytes. The wound healing effect was comparatively evaluated with the standard skin ointment Framycetin.