Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives.

A series of phthalimide-capped benzene sulphonamides (1-22) reported by our group for dengue protease inhibitory activity have been evaluated for their carbonic anhydrase (hCA, EC 4.2.1.1) inhibitory activity against hCA I, hCA II. Compounds 1, 3, 10, and 15 showed hCA I inhibition, whereas 1, 4, and 10 showed hCA II inhibition at nanomolar concentrations. Among these compounds, 1 displayed potent inhibitory activity against the hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM), being 10 and 6 times more potent than acetazolamide, a standard inhibitor (Ki = 250 nM and 12 nM), respectively. Furthermore, this compound displayed 14-fold selectivity towards the hCA II isoform compared to hCA I. Molecular docking and MD simulations were performed to understand the atomic level interactions responsible for the selectivity of compound 1 towards hCA II.

Crystal structures and Hirshfeld surface analyses of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(pyridin-2-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(pyrazin-2-yl)acetamide.

In the title compounds, C11H12N6OS (I) and C10H11N7OS (II), the di-amino-pyrimidine ring makes dihedral angles of 71.10 (9)° with the pyridine ring in (I) and 62.93 (15)° with the pyrazine ring in (II). The ethanamine group, -CH2-C(=O)-NH- lies in the plane of the pyridine and pyrazine rings in compounds (I) and (II), respectively. In both compounds, there is an intra-molecular N-H⋯N hydrogen bond forming an S(7) ring motif and a short C-H⋯O inter-action forming an S(6) loop. In the crystals of both compounds, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with R22(8) ring motifs. In (I), the dimers are linked by N-H⋯O and N-H⋯N hydrogen bonds, forming layers parallel to (1[Formula: see text] [Formula: see text]). The layers are linked by offset π-π inter-actions [inter-centroid distance = 3.777 (1) Å], forming a three-dimensional supra-molecular structure. In (II), the dimers are linked by N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds, also forming a three-dimensional supra-molecular structure.

Crystal structures of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(2,4-di-methyl-phen-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(3-meth-oxy-phen-yl)acetamide.

In the title compounds, C14H17N5OS (I) and C13H15N5O2S (II), the dihedral angle between the pyrimidine and benzene rings is 58.64 (8)° in (I) and 78.33 (9)° in (II). In both compounds, there is an intra-molecular C-H⋯O hydrogen bond, and in (II) there is also an intra-molecular N-H⋯N hydrogen bond present. In the crystals of both compounds, a pair of N-H⋯N hydrogen bonds links the individual mol-ecules to form inversion dimers with R22(8) ring motifs. In (I), the dimers are linked by N-H⋯O and C-H⋯O hydrogen bonds, enclosing R21(14), R21(11) and R21(7) ring motifs, forming layers parallel to the (100) plane. There is also an N-H⋯π inter-action present within the layer. In (II), the inversion dimers are linked by N-H⋯O hydrogen bonds enclosing an R44(18) ring motif. The presence of N-H⋯O and C-H⋯O hydrogen bonds generate an R21(6) ring motif. The combination of these various hydrogen bonds results in the formation of layers parallel to the (1-11) plane.

Crystal structures of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(3-nitro-phen-yl)acetamide monohydrate and N-(2-chloro-phen-yl)-2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]acetamide.

The title compounds, C12H12N6O3S·H2O, (I), and C12H12ClN5OS, (II), are 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]acetamides. Compound (I) crystallized as a monohydrate. In both compounds, the mol-ecules have a folded conformation, with the pyrimidine ring being inclined to the benzene ring by 56.18 (6)° in (I) and by 67.84 (6)° in (II). In both mol-ecules, there is an intra-molecular N-H⋯N hydrogen bond stabilizing the folded conformation. In (I), there is also a C-H⋯O intra-molecular short contact, and in (II) an intra-molecular N-H⋯Cl hydrogen bond is present. In the crystal of (I), mol-ecules are linked by a series of N-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds, forming undulating sheets parallel to the (100). The sheets are linked via an N-H⋯Owater hydrogen bond, forming a three-dimensional network. In the crystal of (II), mol-ecules are linked by a series of N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds, forming slabs parallel to (001).

Progress and prospects on DENV protease inhibitors.

New treatments are desperately required to combat increasing rate of dengue fever cases reported in tropical and sub-tropical parts of the world. Among the ten proteins (structural and non-structural) encoded by dengue viral genome, NS2B-NS3 protease is an ideal target for drug discovery. It is responsible for the processing of poly protein that is required for genome replication of the virus. Moreover, inhibitors designed against proteases were found successful in Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV). Complete molecular mechanism and a survey of inhibitors reported against dengue protease will be helpful in designing effective and potent inhibitors. This review provides an insight on molecular mechanism of dengue virus protease and covers up-to-date information on different inhibitors reported against dengue proteases with medicinal chemistry perspective.

Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies.

The present study evaluates possible drug interactions between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ)-induced diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction based on molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg kg(-1), i.p.) and was confirmed by assessing blood and urine biochemical parameters 28 days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5 mg kg(-1), p.o.) and SIL (2.5 mg kg(-1), p.o.) on the 29th and 70th day of the protocol. Possible drug interaction was assessed by evaluating the plasma drug concentration using HPLC-UV and changes in biochemical parameters in blood and urine were also determined. The mechanism of the interaction was postulated from the results of a molecular modeling study using the Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in blood and urine biochemical parameters in STZ-treated groups. The concentration of SIL increased significantly (P < 0.001) in rat plasma when co-administered with GLIM on the 70th day of the protocol. Molecular modeling revealed important interactions with rat serum albumin and CYP2C9. GLIM has a strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL, whereas for CYP2C9, GLIM forms a stronger hydrogen bond than SIL with polar contacts and hydrophobic interactions. The present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals, and the mechanism is supported by molecular modeling studies.

Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors.

Development of antivirals for dengue is now based on rational approach targeting the enzymes involved in its life cycle. Among the targets available for inhibition of dengue virus, non-structural protein NS2B-NS3 protease is considered as a promising target for the development of anti-dengue agents. In the current study we have synthesized a series of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulphonamide derivatives and screened for DENV2 protease activity. Compounds 16 and 19 showed IC50 of DENV2 Protease activity with 48.2 and 121.9µM respectively. Molecular docking and molecular dynamic simulation studies were carried out to know the binding mode responsible for the activity. MD simulations revealed that, NS2B/NS3 protease was more stable when it binds with the active compound. Structure optimization of the lead compounds 16 and 19 and their co-crystallization studies are underway.

Monoamine oxidase inhibitory activity of 2-aryl-4H-chromen-4-ones.

A series of twenty 2-aryl-4H-chromen-4-one (flavones) derivatives (3a-3s) were synthesized and tested for hMAO inhibitory activity. Fifteen compounds (3a, 3c, 3e-3h, 3j-3p, 3r, 3s) were found to be selective towards MAO-B, while 3d was selective towards MAO-A, and 3b, 3i and 3q were non-selective. Experimental Selectivity Index for MAO-B ranges from 2.0 (3g, 3p) to 30.0 (3j). Compound 3j, which is carrying 3,4-di-OMeC6H3 groups at R position on the molecule, was found to be potent MAO-B inhibitor amongst the fifteen with Ki value for MAO-B of 0.16±0.01 µM comparable to that of standard drug, Selegiline (Ki for MAO-B is 0.16±0.01 µM). Compound 3j also appeared as the most selective MAO-B inhibitor according to its best selectivity index (30.0), which is comparable to that of Selegiline (SIMAO-B=35.0). Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.0 and Amber12 to understand the molecular level interaction and energy relation of MAO isoforms with selective inhibitors (3d and 3j). Simulation results are in good agreement with the experimental results. Leads identified may further be explored to develop potent isoform specific inhibitors of MAO.