3D-QSAR-based design, synthesis and biological evaluation of 2,4-disubstituted quinoline derivatives as antimalarial agents.

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r2ncv = 0.969, q2 = 0.677, r2cv = 0.682) and CoMSIA (r2ncv = 0.962, q2 = 0.741, r2cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC50 values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

Design of 2-amino-6-methyl-pyrimidine benzoic acids as ATP competitive casein kinase-2 (CK2) inhibitors using structure- and fragment-based design, docking and molecular dynamic simulation studies.

Overexpression of casein kinase-2 (CK2) has been implicated in several carcinomas, mainly lung, prostate and acute myeloid leukaemia. The smaller nucleotide pocket compared to related kinases provides a great opportunity to discover newer ATP-competitive CK2 inhibitors. In this study, we have employed an integrated structure- and fragment-based design strategy to design 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive CK2 inhibitors. A statistically significant four features-based E-pharmacophore (ARRR) model was used to screen 780,092 molecules. Further, the retrieved hits were considered for molecular docking study to identify essential binding interactions. At the same time, fragment-based virtual screening was performed using a dataset of 1,542,397 fragments. The identified hits and fragments were used as structure templates to rationalize the design of 2-amino-6-methyl-pyrimidine benzoic acids as newer CK2 inhibitors. Finally, the binding interactions of the designed hits were identified using an induced fit docking (IFD) study, and their stability was estimated by a molecular dynamics (MD) simulation study of 100 ns.

Pharmacophore-based identification and in vitro validation of apoptosis inducers as anticancer agents.

Ligand-based pharmacophore modelling and virtual screening along with in vitro screening were performed as a rational strategy for the identification of novel compounds as apoptosis inducers and anticancer agents from the chemical database. Known apoptosis inducers were selected from the literature for generation of pharmacophore models, which were subjected to validation using Receiver operating characteristic (ROC) and Günere-Henry (GH) scoring methods. Based on highest fitness score of 4680.61, ROC value of 0.872 and GH score of 0.758, pharmacophore model-2 was selected as the best model. Model-2 as 3D search query was searched against the IBS database to find novel compounds as hits. Three hits were selected with a QFIT value more than 82 for in vitro screening as apoptosis inducers and anticancer agents. In vitro anticancer activity was performed using resazurin cell variability assay, and apoptosis inducing activity was determined using caspase-3 activation and annexin-FITC assays. One of the retrieved hit, STOCK5S-44056 demonstrated IC50 value of 23.56 µM in cell variability assay, and had EC50 value of 26.95 µM in caspase-3 activation assay. STOCK5S-44056 also indicated late stage induction of apoptosis in annexin assay. The results of in vitro activity revealed that STOCK5S-44056 has a potential to become anticancer agents.

Three's a Crowd - An Extremely Rare Case of Cor Triatriatum Dexter.

INTRODUCTION: Cor triatriatum is a congenital cardiac anomaly in which the left (sinister) or right (dexter) atrium is divided into two compartments by residual embryonic tissue, resulting in a tri-atrial heart. As cor triatriatum dextrum can present clinically in various ways and have multiple associated cardiac anomalies, this report attempts to contribute to what is known about this exceedingly rare disorder. CASE: A 40 year old Hispanic man with a medical history of gastritis presented with complaints of palpitations, dizziness and bilateral lower extremity edema. He was found to have atrial fibrillation and new onset heart failure. The patient was admitted for rate control and further evaluation, which revealed several cardiac anomalies. Initial 2D echocardiography demonstrated severe right atrial enlargement, right ventricular hypertrophy and an engorged coronary sinus, which prompted further assessment of the patient's cardiovascular anatomy. Transesophageal echocardiography (TEE) revealed a severely enlarged, septated right atrium with a possible unroofed coronary sinus and a small patent foramen ovale (PFO). Left- and right-heart catheterization established a coronary-cameral fistula between the right coronary artery (RCA) and right atrium, as well as left-to-right shunt. The patient improved clinically with conservative management including diet modification, furosemide and digoxin for fluid and rate control, and was referred to cardiothoracic surgery for further evaluation. DISCUSSION: Cor triatriatum dextrum is an extremely rare cardiac condition: In high-volume echocardiographic laboratories, prevalence is less than 0.01 percent. This case highlights the association between cor triatriatum and other congenital cardiac anomalies, including persistent left superior vena cava with an unroofed coronary sinus, PFO and left-to-right shunt; all of which were found in this patient. While cases of cor-triatriatum sinistrum often require correction in infancy (due to left sided heart failure, pulmonary edema and cyanosis), cor-triatriatum dextrum is sometimes diagnosed in adulthood due to the lack of left heart and pulmonary involvement.

Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 µM to 142 µM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere-Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.

Surface display of Aggregatibacter actinomycetemcomitans autotransporter Aae and dispersin B hybrid act as antibiofilm agents.

Among the various proteins expressed by the periodontopathogen Aggregatibacter actinomycetemcomitans, two proteins play important roles for survival in the oral cavity. The autotransporter Aae facilitates the attachment of the pathogen to oral epithelial cells, which act as a reservoir, while the biofilm-degrading glycoside hydrolase dispersin B facilitates the movement of daughter cells from the mature biofilm to a new site. The objective of this study was to use the potential of these two proteins to control biofilms. To this end, we generated a hybrid construct between the Aae C-terminal translocating domain and dispersin B, and mobilized it into Escherichia coli Rosetta (DE3) pLysS cells. Immunofluorescence analysis of the modified E. coli cells confirmed the presence of dispersin B on the surface. Further, the membrane localization of the displayed dispersin B was confirmed with Western blot analysis. The integrity of the E. coli cells displaying the dispersin B was confirmed through FACS analysis. The hydrolytic activity of the surface-displayed dispersin B was confirmed by using 4-methylumbelliferyl-ß-d-glucopyranoside as the substrate. The detachment ability of the dispersin B surface-displaying E. coli cells was shown using Staphylococcus epidermidis and Actinobacillus pleuropneumoniae biofilms in a microtiter assay. We concluded that the Aae ß-domain is sufficient to translocate foreign enzymes in the native folded form and that the method of Aae-mediated translocation of surface displayed enzymes might be useful for control of biofilms.

FOOD FOR THOUGHT: MITRAL STENOSIS WITH A SIDE OF MAC AND CHEESE.

Caseous mitral annular calcification (CMAC) is a rare variant of mitral annular calcification (MAC), most commonly seen in elderly women on the posterior mitral annulus. CMAC is usually diagnosed incidentally and has a benign course. However, it may cause abnormal blood flow across the mitral valve resulting in mitral regurgitation, and rarely, functional mitral stenosis. MAC occurs in 10 percent of the population, while CMAC occurs in 0.06 percent. Most cases of CMAC are misdiagnosed as other intracardiac masses, such as tumors, abscesses, thrombi, and vegetation.

Design, synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonists based on predictive 3D QSAR models.

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII-AT1 receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII-AT1 receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q(2)) of 0.630 and 0.623, respectively, cross-validated coefficients (r(2)cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r(2)) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r(2)pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT1 receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II-AT1 receptor antagonism.

Development of docking-based 3D QSAR models for the design of substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors.

This study has investigated docking-based 3D quantitative structure-activity relationships (QSARs) for a range of quinoline carboxylic acid derivatives by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). A docking study has shown that most of the compounds formed H-bonds with Arg136 and Gln47, which have already been shown to be essential for the binding of ligands at the active site of the hydroorotate dehydrogenase adenovirus (hDHODH). Bioactive conformations of all the molecules obtained from the docking study were used for the 3D QSAR study. The best CoMFA and CoMSIA models were obtained for the training set and were found to be statistically significant, with cross-validated coefficients (q²) of 0.672 and 0.613, r² cv of 0.635 and 0.598 and coefficients of determination (r²) of 0.963 and 0.896, respectively. Both models were validated by a test set of 15 compounds, giving satisfactory predicted correlation coefficients (r² pred) of 0.824 and 0.793 for the CoMFA and CoMSIA models, respectively. From the docking-based 3D QSAR study we designed 34 novel quinoline-based compounds and performed structure-based virtual screening. Finally, in silico pharmacokinetics and toxicities were predicted for 24 of the best docked molecules. The study provides valuable information for the understanding of interactions between hDHODH and the novel compounds.

CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents.

SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q²) of 0.602 and 0.618, respectively, and conventional coefficients (r²) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r² pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.

Homology modeling a fast tool for drug discovery: current perspectives.

Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery.

Nanofiber-nanorod composites exhibiting light-induced reversible lower critical solution temperature transitions.

Stimuli-responsive materials are promising as smart materials for a range of applications. In this work, a photo-crosslinkable, thermoresponsive macromer was electrospun into fibrous scaffolds containing gold nanorods (AuNRs). The resulting fibrous nanocomposites composed of poly(N-isopropylacrylamide-co-polyethylene glycol acrylate) (PNPA) and PEGylated AuNRs were crosslinked and swollen in water. AuNRs strongly absorb in the near-infrared (NIR) region to generate heat, which triggered the fiber thermal transition upon NIR light exposure. During the thermal transition, scaffolds collapsed both macroscopically and microscopically, with individual fibers deswelling and pulling together. Exposure to a 1.1 W NIR laser decreased the diameter of swollen fibers by 34.7% from 1332 ± 193.3 to 868.9 ± 168.3 nm, and increased fiber density 116% from 209.5 ± 26.34 to 451.9 ± 23.68 fibers mm( - 1). This transition was dependent on the incorporation of the AuNRs, and was utilized to trigger the release of encapsulated proteins from the nanocomposite fiber mats. The expulsion of water from fibers upon NIR exposure caused the release rate of incorporated protein to increase greater than tenfold, from 0.038 ± 0.052 without external stimulus to 0.462 ± 0.227 µg protein/mg polymer/min with NIR exposure. These results suggest that light-responsive fibrous nanocomposites can be utilized in applications such as drug delivery.

Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors.

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.

Unique presentation of maxillary artery, lingual nerve, and inferior alveolar nerve complex.

Knowledge of variations in arteries and nerves of infratemporal fossa may be helpful in radical neck dissection and in dental procedures to avoid the complications. We present an unusual case in which maxillary artery was found deep (medial) to lateral pterygoid muscle. Lingual nerve originated from two roots: anterior and posterior. Anterior root originated from common trunk and the posterior root directly from mandibular nerve. Inferior alveolar nerve was a continuation of the common trunk. Branches of mandibular nerve formed a loop through which passed the second part of maxillary artery. The clinical significance of the present variations has been discussed.

Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review.

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT(1) receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT(1) receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocyclic such as imidazole (losartan) and benzimidazole (candesartan and telmisartan). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II-AT(1) receptor antagonists and explored other potential clinical uses for this class of compounds.

Proton magnetic resonance ((1)HNMR) spectroscopy and physicochemical studies of zaleplon-hydroxypropyl-ß-cyclodextrin inclusion compounds.

Proton magnetic resonance spectroscopy ((1)HNMR) studies on inclusion compounds of zaleplon with hydroxypropyl-ß- cyclodextrin (HPßCD) were carried out in order to elucidate the strength and binding mode of association. Chemical shift measurements revealed that inclusion complexes of zaleplon and HPßCD were formed by penetration of aromatic rings into the HPßCD cavity from the wider rim side with deep penetration of the amide-substituted ring while inclusion of the cyano-substituted pyrazole ring was shallow. A higher magnitude of ΔδH-3' and ΔδH-5' protons of HPßCD indicated higher stability of the lyophilized product than the kneaded one. Even from the values of ΔδH-5'/ΔδH-3', it could be concluded that zaleplon deeply penetrated inside the HPßCD cavity in the lyophilized product as compared to the kneaded product. The stoichiometry of the inclusion complexes was assessed to be a 1:1 molar ratio with an AL-type of phase solubility curve and a stability constant of 57.89 ± 1.82 M-1, according to Higuchi and Connors. In the case of dissolution experiments, a lyophilized product displayed a higher release rate of zaleplon (DE30: 77.64 ± 5.74) than the kneaded complex and physical mixture.

Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe.

Solid dispersions of the poorly water-soluble drug ezetimibe were prepared with a surfactant, Pluronic 188 in different ratios and characterized by FTIR, XRD, DSC and dissolution studies. The melting method was employed to prepare the solid dispersions whereas a physical mixture (1:3) was prepared by co-grinding the individual components in a mortar. Physical studies demonstrated a significant reduction in crystallinity with a possibility of presence of amorphous character of drug in the solid dispersions of ezetimibe. Among all binary systems studied, the 1:3 proportion of ezetimibe: Pluronic 188 showed fastest dissolution rate (DE90: 73.38% +/- 3.95) suggesting optimum ratio of the surfactant used.

Development and characterization of bicalutamide-poloxamer F68 solid dispersion systems.

The objective of the present work was to improve the dissolution rate of a poorly water-soluble drug, bicalutamide, by a solid dispersion technique. The solid dispersion systems of bicalutamide were prepared with poloxamer F68 in 1:1, 1:3, and 1:5 ratios using the melting method. The interaction of drug with polymer was evaluated by TLC, FTIR, and powder XRD. The results of powder XRD showed a significant decrease in the crystallinity of drug in the binary systems of bicalutamide. All binary systems of bicalutamide showed faster dissolution than pure drug alone (p < 0.001). However, among all binary systems studied, 1:1 proportion of bicalutamide : poloxamer was found to be excellent for dissolution enhancement (DP30: 99.98% +/- 3.9) of bicalutamide. The higher ratios of poloxamer F68 (1:3 and 1:5) had retarded the release of drug from their corresponding binary systems which might be due to its gelling property in higher concentration.

Primary mediastinal pleomorphic rhabdomyosarcoma: a case report.

OBJECTIVE: To report a rare case of pleomorphic rhabdomyosarcoma which occurred in the mediastinum of a 34-year-old man. CLINICAL PRESENTATION AND INTERVENTION: A young male labourer presented with dyspnoea on exertion. A large mediastinal mass was detected on chest CT scan. The chest surgeons advised against open biopsy. His alpha-fetoprotein was 22,000 IU/l; based on this the diagnosis of a germ cell tumour was made and the patient was treated with a bleomycin/etoposide/cisplatin regimen. He left for his native country where an open biopsy from the mediastinum was taken and reported as pleomorphic rhabdomyosarcoma. He was given five courses of chemotherapy with doxorubicin, etoposide, and ifosfamide with mesna protection without much relief. The inoperable disease occupied the whole of the right chest and mediastinum. The enormous size of the radiation field made radiotherapy prohibitive. Finally, the patient opted for symptomatic treatment and left for his native place. CONCLUSION: This case is presented because of its difficulty in management and rarity.