Design, synthesis, and computational studies of phenylacetamides as antidepressant agents.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.

Validation of a Deep Learning Model for Detecting Chest Pathologies from Digital Chest Radiographs.

Purpose: Manual interpretation of chest radiographs is a challenging task and is prone to errors. An automated system capable of categorizing chest radiographs based on the pathologies identified could aid in the timely and efficient diagnosis of chest pathologies. Method: For this retrospective study, 4476 chest radiographs were collected between January and April 2021 from two tertiary care hospitals. Three expert radiologists established the ground truth, and all radiographs were analyzed using a deep-learning AI model to detect suspicious ROIs in the lungs, pleura, and cardiac regions. Three test readers (different from the radiologists who established the ground truth) independently reviewed all radiographs in two sessions (unaided and AI-aided mode) with a washout period of one month. Results: The model demonstrated an aggregate AUROC of 91.2% and a sensitivity of 88.4% in detecting suspicious ROIs in the lungs, pleura, and cardiac regions. These results outperform unaided human readers, who achieved an aggregate AUROC of 84.2% and sensitivity of 74.5% for the same task. When using AI, the aided readers obtained an aggregate AUROC of 87.9% and a sensitivity of 85.1%. The average time taken by the test readers to read a chest radiograph decreased by 21% (p < 0.01) when using AI. Conclusion: The model outperformed all three human readers and demonstrated high AUROC and sensitivity across two independent datasets. When compared to unaided interpretations, AI-aided interpretations were associated with significant improvements in reader performance and chest radiograph interpretation time.

Three-dimensional quantitative structure-activity relationship of interleukin 1-beta converting enzyme inhibitors: A comparative molecular field analysis study.

A three-dimensional quantitative structure-activity relationship (QSAR) study using the comparative molecular field analysis (CoMFA) method was performed on a series of interleukin 1-beta converting enzyme (ICE) inhibitors. The compounds studied have been reported to be time-dependent inhibitors of ICE. This study was performed using 49 compounds, in which the CoMFA models were developed using a training set of 39 compounds. All the compounds were modeled using the X-ray crystal structure of tetrapeptide aldehyde inhibitor/ICE complex. The inhibitor compounds were considered both as neutral species and as P1 carboxylate ionized species. Superimpositions were performed using two alignment rules, namely, an alignment of the structures based on RMS fitting of the backbone heavy atoms of each structure to compound 2 and an alignment based on SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules to the fields of compound 2. Use of LUMO energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the CoMFA models. Steric and electrostatic fields of the inhibitors were found to be the relevant descriptors for structure-activity relationships. The predictive ability of the CoMFA model was evaluated by using a test set of 10 compounds (r2pred as high as 0.859). Further comparison of the coefficient contour maps with the steric and electrostatic properties of the receptor show a high level of compatibility.

Comparative molecular field analysis of fungal squalene epoxidase inhibitors.

Comparative molecular field analysis (CoMFA) of fungal squalene epoxidase inhibitors exhibiting antifungal activity reported in terms of minimum inhibitory concentration (MIC) was performed. Ninety-two molecules belonging to different chemical classes, namely terbinafine analogues, benzylamines, homopropargylamines, and carbon analogues were divided into training set and test set. The initial conformations of the inhibitors obtained from molecular dynamics simulations for 50 ps in aqueous solution were used in the study. Out of three charges used in the study, Gasteiger-H]uckel charges result in models with good internal predictivity. Initial analysis of 92 molecules (analysis A) resulted in models with low predictive r(2) values for activity against three organisms. This data set was modified by exclusion of 13 molecules, and analysis was performed again. This analysis of 79 molecules (analysis B) resulted in improvement in predictivity of the CoMFA models and cross-validated r(2) values of 0.583, 0.509, and 0.502 for Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes, respectively. These models were used to predict the activities of the molecules belonging to the test set. The models from analysis B show better correlative and predictive properties than analysis A. Comparison of CoMFA contour maps for activity against three different fungi revealed differentiating structural requirements.

Conformational studies of antiradiation agents by NMR: cysteamine and its derivatives.

The conformations of cysteamine, thiazolidine, and thiazolidine-4-carboxylic acid were determined in aqueous solutions using NMR spectroscopy. At physiological pH, the population ratio of gauche- and trans-conformers was 3:1. The gauche-rotamer is probably responsible for the antiradiation activity and acts through metal chelation involving sulfur and nitrogen atoms. The puckering of the thiazolidine ring was calculated using NMR coupling constants. The observed results were compared with those obtained in the solid state using X-ray diffraction.

A feature based pharmacophore for Candida albicans MyristoylCoA: protein N-myristoyltransferase inhibitors.

A three-dimensional pharmacophore model has been generated for Candida albicans MyristoylCoA: protein N-myristoyltransferase (NMT) inhibitors, using the software program CATALYST. The in vitro NMT inhibitory activity of a series of peptidic inhibitors was used for pharmacophore generation. The effect of altering the control parameters and feature selection was studied to arrive at the pharmacophore model. The selection of the best hypothesis model was based on the total cost, predictive ability, difference in the cost from the null hypothesis and alignment of the training set compounds on to the hypothesis. The pharmacophore model selected has four features; one hydrophobic, two hydrogen bond acceptor and one positive ionisable function. Groups identified as necessary by scanning alanine mutagenesis studies of the peptidic substrate of C. albicans NMT, have been identified as pharmacophore features. Comparison of the ligand binding with the enzyme in the crystal structure of NMT and that proposed by the phamacophore is consistent. The pharmacophore thus generated can be used as a template for designing non-peptidic inhibitors of NMT.

Use of adrenal vein conduit for splenorenal shunts: a case report.

We report a case with extrahepatic portal venous obstruction (EHPVO), who presented with recurrent bleeding following a previous devascularization procedure and needed an emergency distal spleno-renal shunt (DSRS). Due to technical difficulty because of previous scarring, the adrenal vein was used as a conduit between the splenic vein and renal vein. The shunt's patent and the patient has been bleed-free for 2 years.

Chemical drug delivery systems: I. Preparation and evaluation of prodrugs of dapsone.

Several prodrugs of dapsone have been prepared and evaluated in vivo for the release of parent drug. The prodrug: 4,4'-dibutyrylaminodiphenyl sulfone gave blood levels above 0.5 micrograms/ml of DDS for about 34 days in rabbits injected intragluteally. The results have been compared with DDS and DADDS.

Conformational studies on cimetidine and ranitidine by PCILO calculations and NMR spectroscopy.

The conformational characteristics of two H2-receptor antagonists, cimetidine and ranitidine, have been investigated by quantum mechanical PCILO method and the results indicate a folded conformation for cimetidine stabilized by intramolecular hydrogen bonding and an extended backbone conformation for ranitidine. NMR investigations carried out on these two drugs in solution, however, indicate a predominance of an extended conformation for both the molecules. The significance of this result has been discussed in terms of the activity of these two drugs. Besides these studies, NMR experiments have also been carried out on the drugs incorporated into the lipid bilayers to investigate the drug-lipid interaction. The results from this study suggest that the hydrophobic portion of the drugs is buried in the hydrophobic hydrocarbon chains of the lipid bilayer, while the terminal hydrophilic end of the drug lies at the lipid-water interface.

Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors.

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.

Case based measles surveillance in Pune: evidence to guide current and future measles control and elimination efforts in India.

BACKGROUND: According to WHO estimates, 35% of global measles deaths in 2011 occurred in India. In 2013, India committed to a goal of measles elimination by 2020. Laboratory supported case based measles surveillance is an essential component of measles elimination strategies. Results from a case-based measles surveillance system in Pune district (November 2009 through December 2011) are reported here with wider implications for measles elimination efforts in India. METHODS: Standard protocols were followed for case identification, investigation and classification. Suspected measles cases were confirmed through serology (IgM) or epidemiological linkage or clinical presentation. Data regarding age, sex, vaccination status were collected and annualized incidence rates for measles and rubella cases calculated. RESULTS: Of the 1011 suspected measles cases reported to the surveillance system, 76% were confirmed measles, 6% were confirmed rubella, and 17% were non-measles, non-rubella cases. Of the confirmed measles cases, 95% were less than 15 years of age. Annual measles incidence rate was more than 250 per million persons and nearly half were associated with outbreaks. Thirty-nine per cent of the confirmed measles cases were vaccinated with one dose of measles vaccine (MCV1). CONCLUSION: Surveillance demonstrated high measles incidence and frequent outbreaks in Pune where MCV1 coverage in infants was above 90%. Results indicate that even high coverage with a single dose of measles vaccine was insufficient to provide population protection and prevent measles outbreaks. An effective measles and rubella surveillance system provides essential information to plan, implement and evaluate measles immunization strategies and monitor progress towards measles elimination.

Novel curcumin analogs targeting TNF-induced NF-kappaB activation and proliferation in human leukemic KBM-5 cells.

Novel curcumin analogs were synthesized using Knoevenagel condensation to convert enolic diketones of curcumin into non-enolizable ones and Schiff bases were prepared using a bioactive thiosemicarbazide pharmacophore. Copper(II) conjugates of all synthesized ligands were prepared and structurally characterized as well as evaluated for their potential of inhibiting TNF-induced NF-kappaB activation and proliferation in human leukemic KBM-5 cells wherein compound 13 was found to be more potent than curcumin. Compounds were further examined on other tumor cell lines such as Jurkat, H1299, and MM1, respectively.

Eigen value analysis of HIV-1 integrase inhibitors.

A three-dimensional quantitative structure activity relationship using the eigen value analysis (EVA) paradigm applied to 41 HIV-1 integrase inhibitors that inhibit integrase mediated cleavage (3'-processing step) and integration (3'-strand transfer step) in vitro was performed. The training set consisted of 35 molecules from five structurally diverse classes: salicylhydrazines, lichen acids, coumarins, quinones, and thiazolothiazepines. Models derived using semiempirical (MOPAC AM1 and PM3) calculated normal-mode frequencies were compared. The predictive ability of each resultant model was evaluated using a test set comprised of six molecules belonging to a different structural class: hydrazides. Models derived using AM1 method showed considerable internal as well as external predictivity (r(2)(cv) = 0.806, r(2)(pred) = 0.761 for 3'-processing and r(2)(cv) = 0.677, r(2)(pred) = 0.591 for 3'-strand transfer).

A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists.

Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods of identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to 13 diverse sets of compounds showing different levels of biological activity. A systematic conformational analysis was carried out to obtain sterically accessible conformations for these flexible compounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimized AM1) from each compound's data set that best fits the biophoric pattern and the resulting superimposition with all the other data-set compounds. Apex-3D identified three common biophoric features important for activity: one as the hydroxyl, acetyl, carbonyl and carboxyl groups, which mimic the acid-binding region of an agonist, the other as the hydrogen-bond donating site, and the third part is represented by a plane in which lipophilic aromatic groups align. The structure-activity relationships were then assessed by using the 3D-QSAR model. A common biophore model is proposed from the Apex-3D analysis which may be useful in designing new pLT antagonists. Molecular volumes and electrostatic potential similarities were also calculated in order to obtain the important structural requirements for the activity.

A molecular dynamics study of the three-dimensional model of human synovial fluid phospholipase A2--transition state mimic complexes.

Different modes of binding of transition state mimics: amide, phosphonate and difluoro ketone, to human synovial fluid phospholipase A2 (HSF PLA2) are studies by molecular dynamics simulations computed in solvent. The results are analysed in the light of primary binding sites. Hydrogen bonding interaction plays an important role for amino acids such as Gly32, Val30, and Glu55, apart from the well known active site residues viz Asp48, Gly25, Gly29, Gly31, His27, His47, Lys62, Phe23, Asn114 and Tyr112. In addition, the hydrogen bonding interaction between Sn-1 tetrahedral phosphonate group of amide and difluoro ketone inhibitors and crystallographic water molecules (H2O 523, H2O 524 and H2O 401) seems to have a significant role. Many of the active site charged residues display considerable movement upon ligand binding. The structural effects of ligand binding were analyzed from RMS deviations of C alpha in the resulting energy-minimized average structures of the receptor-ligand complexes. The values of the RMS deviations differ among the HSF PLA2s, in a pattern that is not the same for the three complexes. This suggests that ligands with different pharmacological efficacies induce different types of conformational changes of the receptor. Our active-orientation model is, at least qualitatively, consistent with experimental data and should be useful for the rational design of more potent inhibitors.

Three-dimensional quantitative structure-activity relationship (QSAR) and receptor mapping of cytochrome P-450(14 alpha DM) inhibiting azole antifungal agents.

Molecular modeling was performed by a combined use of conformational analysis and 3D-QSAR methods to distinguish structural attributes common to a series of azole antifungal agents. Apex-3D program was used to recognize the common biophoric structural patterns of 13 diverse sets of azole antifungal compounds demonstrating different magnitudes of biological activity. Apex-3D identified three common biophoric features significant for activity: N1 atom of azole ring, the aromatic ring centroid 1, and aromatic ring centroid 2. A common biophore model proposed from the Apex-3D analysis can be useful for the design of novel cytochrome P-450(14 alpha DM) inhibiting antifungal agents.

Inhibitory activity and mode of action of diaminodiphenylsulfone in cell-free folate-synthesizing systems prepared from Mycobacterium lufu and Mycobacterium leprae. A comparison.

Cell-free folate synthesizing extracts have been isolated from Escherichia coli, Mycobacterium lufu, Mycobacterium smegmatis (ATCC 607) and Mycobacterium leprae, and the inhibitory power of diaminodiphenylsulfone (DDS) in such cell-free systems on the synthesis of dihydropteroic acid has been determined. M. lufu and M. leprae extracts show very similar high sensitivities against DDS. Mode of action studies seem to indicate that the observed high sensitivity of M. lufu and M. leprae as compared to E. coli can be solely attributed to a high affinity for the dihydropteroic acid synthetase. A dihydropteroic acid analog formation where DDS is incorporated instead of p-aminobenzoic acid--as has been observed in E. coli--could not be detected.

Structure based prediction of binding affinity of human immunodeficiency virus-1 protease inhibitors.

A series of computations were performed to derive a strategy for the prediction of binding affinities of non-peptidic human immunodeficiency virus-1 (HIV-1) protease inhibitors. This paper describes the development of a 3D quantitative structure-activity relationship (3D-QSAR) methodology by using receptor information of HIV-1 protease. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. The protonation scheme of the active site aspartic acid residues of HIV-1 protease was derived from a computational study. The active site aspartate is monoprotonated with a proton placed on the OD1 atom of the ASP B25. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand-enzyme complexes of the molecules used in the present study. The molecular mechanics interaction descriptors were calculated from these ligand/enzyme models. A partial least squares (PLS) method was used to derive a linear correlation between the interaction descriptors and the biological activity. A good correlation was observed when the change in the energy of the ligand upon complex formation and the electrostatic contributions to the solvation energy of the ligand were included in the QSAR analysis. A highest cross-validated q2 value of 0.649 was observed. This model had a conventional r2 of 0.725, and when this model was used to predict the activity of the external test set, it produced a r2pred of 0.761. The total interaction energy was partitioned into interactions in different subsites and interactions with each of the amino acid residues of the enzyme. The PLS analysis using these descriptors helped to identify the important interactions which can be exploited for the design of HIV-1 protease inhibitors.

Molecular electrostatic potentials as input for the alignment of HIV-1 integrase inhibitors in 3D QSAR.

Comparative molecular similarity indices analysis (CoMSIA), a three-dimensional quantitative structure activity relationship (3D QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities (3'-processing and 3'-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. The training set consisted of 34 molecules from five structurally diverse classes: salicylpyrazolinones, dioxepinones, coumarins, quinones, and benzoic hydrazides. The data set was aligned using extrema of molecular electrostatic potentials (MEPs). The predictive ability of the resultant model was evaluated using a test set comprised of 7 molecules belonging to a different structural class of thiazepinediones. A CoMSIA model using an MEP-based alignment showed considerable internal as well external predictive ability (r2(cv) = 0.821, r2(pred) = 0.608 for 3'-processing; and r2(cv) = 0.759, r2(pred.) = 0.660 for 3'-strand transfer).