Exploration of Diosmin to Control Diabetes and Its Complications-an In Vitro and In Silico Approach.

BACKGROUND: Diosmin is a flavonoid obtained from the citrus fruits of the plants. Diosmin has blood lipid lowering activities, antioxidant activity, enhances venous tone and microcirculation, protects capillaries, mainly by reducing systemic oxidative stress. OBJECTIVE: The present study demonstrates the potential of Diosmin against the enzymes aldose reductase, α-glucosidase, and α-amylase involved in diabetes and its complications by in vitro evaluation and reverse molecular docking studies. METHODS: The assay of aldose reductase was performed by using NADPH as starting material and DL-Glyceraldehyde as a substrate. DNS method was used for alpha amylase inhibition and in alpha glucosidase inhibitory activity p-nitrophenyl glucopyranoside (pNPG) was used as substrate. The reverse molecular docking studies was performed by using Molegro software (MVD) with grid resolution of 30 Å. RESULTS: Diosmin shows potent inhibitory effect against aldose reductase (IC50:333.88±0.04 µg/mL), α-glucosidase (IC50:410.3±0.01 µg/mL) and α-amylase (IC50: 404.22±0.02 µg/mL) respectively. The standard drugs shows moderate inhibitory activity for enzymes. The MolDock Score of Diosmin was -224.127 against aldose reductase, -168.17 against α-glucosidase and - 176.013 against α-amylase respectively, which was much higher than standard drugs. CONCLUSION: From the result it was concluded that diosmin was a potentially inhibitor of aldose reductase, alpha amylase and alpha glucosidase enzymes then the standard drugs and it will be helpful in the management of diabetes and its complications. This will also be benevolent to decrease the socio economical burden on the middle class family of the society.

2-(pyrazin-2-yloxy)acetohydrazide analogs QSAR Study: An insight into the structural basis of antimycobacterial activity.

Quantitative structure activity relationship analysis based on classical Hansch approach was adopted on reported novel series of 2-(pyrazin-2-yloxy)acetohydrazide analogs. Various types of descriptors like topological, spatial, thermodynamic, and electronic were used to derive a quantitative relationship between the antitubercular activity and structural properties. The consensus scoring function showed a significant statistics of training and test set. Coefficient of determination (r²) of consensus model and predictive squared correlation coefficient (r²(pred)) were found to be 0.889 and 0.782, respectively. The model is not only able to predict the activity of test compounds but also explained the important structural features of the molecules in a quantitative manner. The study revealed that antimycobacterium activity is predominantly explained by the molecular connectivity indices of length 6, hydrogen donor feature of the analogs, and shape factors of the substituent. The comparative investigation of antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhi provided structural insights on how modulation of the molecular connectivity indices, energy of lowest unoccupied molecular orbital, accessible surface area, and moment of inertia of the analogs could be usefully made to optimize the antibacterial activity.

Insights through AM1 calculations into the structural requirement of N-hydroxythiosemicarbazone analogs as anti-tubercular agents.

Fujita-Ban, Hansch substituent constants, topological descriptors and conformational dependent descriptors were explored for quantification of anti-tubercular activity of N-hydroxythiosemicarbazone analogs. All the approaches gave statistically sound model which accounts for more than 88% of the explain variance against anti-tubercular activity except Fujita-Ban (approximately 75%). Fujita-Ban & Hansch approaches having certain limitation, however, another approache showed their significant role in explaining activity of the modified scaffolds. QSAR study of N-Hydroxythiosemicarbazone analogs furnished some important structural insights i.e., the R position is more prone for improving inhibitory activity and the R(1) position play a decisive role in the ionic interaction of the ligand with macromolecules. On the basis of findings, N-hydroxythiosemicarbazones interaction model with macromolecule of M. Tuberculosis has been proposed. These interactions might be helpful in further development of potent anti-tubercular agents.

Exploration of physicochemical properties and molecular modelling studies of 2-sulfonyl-phenyl-3-phenyl-indole analogs as cyclooxygenase-2 inhibitors.

In the present work, modelling study has been performed to explore the physicochemical requirements of 2-sulfonyl-phenyl-3-phenyl-indole analogs as COX-2 enzyme inhibitors. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) technique, considering adjustable correlation coefficient (r(adj)(2)). The statistical quality of SEQ-MLR equations was evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF). Developed equations have been internally validated using leave-one-out technique and further validated with test set, considering predictive squared correlation coefficient (r(pred)(2)). The orientation of the most potent and selective COX-2 inhibitor of training set, 2-(4-phenyl sulfonamide)-3-phenyl-5-methylindole, in the COX-2 active site was explored by docking. The phenyl sulfonamide moiety positioned in secondary pocket of enzyme which consists of amino acid residues Phe(518), Gln(192), Arg(513), Leu(352), Ser(353) and Val(523) is responsible for the selectivity. The unsubstituted phenyl ring positions in a hydrophobic cavity are lined by Tyr(385), Trp(387), Tyr(348), Leu(384) and Met(522). Interestingly, the indole C-5 CH(3)-substituent is located in a hydrophobic region formed by Ile(345), Val(349), Ala(527), Leu(531) and Leu(534). The hydrophobic interactions of methyl group might be crucial for the potency of 2-sulfonyl-phenyl-3-phenyl-indole analogs. Study has revealed that atomic van der Waals volume and atomic masses explain COX-2 inhibitory activity of 2-sulfonyl-phenyl-3-phenyl-indole analogs significantly.

Rationalization of physicochemical characters of oxazolyl thiosemicarbazone analogs towards multi-drug resistant tuberculosis: a QSAR approach.

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis and the continuing pandemic of tuberculosis emphasizes the urgent need for the development of new and potent anti-tubercular agents. In an effort to develop new and more effective agents to treat tuberculosis emphasis was focused on quantification of structure-activity relationship of oxazolyl thiosemicarbazone derivatives. The de novo analysis gave insight to some important structural features i.e. nitro group on phenyl ring at R(1) position is optimal for the activity and might be responsible for electronic interaction, while phenyl ring at R position interact with the hydrophobic pocket more effectively as compared to unsubstituted or methyl substituted analogs. Hansch approach offered the understanding and parameterization of interactions of the inhibitor with receptor. Similarly QSAR analysis gave some important physicochemical properties, i.e. empirical aromatic index (ARR) and 3D-MoRSE code value of scattering angle at 8A(-1). These two physicochemical properties shall be helpful in the development of more potent analogs.