Metal resistance in Acinetobacter and its relation to β-lactamase production

Thirty nine clinical isolates of Acinetobacter belonging to six species were tested for resistance to 20 metal ions and their ability to produce -lactamase. Fifty two percent of the strains produced -lactamase. -Lactamase producers and non-producers were almost equally distributed in the different species. A. baumannii was the predominant biotype and was found to be most resistant to metals. Resistance to mercury was prevalent in -lactamase-producing A. baumannii only. Silver resistant strains of A. baumannii produced -lactamase. Sensitivity and resistance to copper and cadium was equally distributed between -lactamase producers and non-producers. -Lactamase-producer and -non-producer strains were uniformly sensitive to cadmium except Acinetobacter genospecies 1.     

Energetic salts from nitroformate ion

Development of new energetic salts is the key factor in replacing low performance compounds in conventional formulations of high explosives as well as propellants. Ten salts based on the nitroformate anion and various nitrogen-rich cations were designed and their geometric optimizations carried out using the density functional method. With reasonable oxygen balance (from ?36 % to 0 %), heats of formation (47–624 kJ mol^?1) and high densities (1.81–1.89 g cm^?3), the detonation velocity (D) and pressure (P) values of salts were calculated as 8.62–9.36 km s^?1 and 33.10–40.01 GPa, respectively. Lastly, the nitroformate salts studied in this work are of prospective interest as high performance explosives.

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Graphical Abstract Formation of nitroformate salt from nitroformate anion and a nitrogen-rich cation

     

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.     

Theoretical studies on nitrogen rich energetic azoles

Different nitro azole isomers based on five membered heterocyclics were designed and investigated using computational techniques in order to find out the comprehensive relationships between structure and performances of these high nitrogen compounds. Electronic structure of the molecules have been calculated using density functional theory (DFT) and the heat of formation has been calculated using the isodesmic reaction approach at B3LYP/6-31G* level. All designed compounds show high positive heat of formation due to the high nitrogen content and energetic nitro groups. The crystal densities of these energetic azoles have been predicted with different force fields. All the energetic azoles show densities higher than 1.87 g/cm³. Detonation properties of energetic azoles are evaluated by using Kamlet-Jacobs equation based on the calculated densities and heat of formations. It is found that energetic azoles show detonation velocity about 9.0 km/s, and detonation pressure of 40GPa. Stability of the designed compounds has been predicted by evaluating the bond dissociation energy of the weakest C-NO₂ bond. The aromaticity using nucleus independent chemical shift (NICS) is also explored to predict the stability via delocalization of the π-electrons. Charge on the nitro group is used to assess the impact sensitivity in the present study. Overall, the study implies that all energetic azoles are found to be stable and expected to be the novel candidates of high energy density materials (HEDMs).     

Computational design and structure–property relationship studies on heptazines

This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting systematic structure–property relationships. Molecular structures with diverse energetic substituents at varying positions in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm⁻³, and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics. The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas generators and smoke-free pyrotechnic fuels as they are rich in nitrogen content.     

A new species of Rhabdochona Railliet, 1916 (Nematoda: Rhabdochonidae) from cyprinid fishes in the Western Ghats Region,India

A new nematode species, Rhabdochona (Globochona) puntii n. sp. (Rhabdochonidae), is described based on specimens collected from the intestine of the pool barb Puntius sophore (Hamilton) and Neolissochilus hexastichus (McClelland) (both Cyprinidae) from the Gadhena River, the Western Ghats, Maharashtra State, India. The nematode was also found in Wallago attu (Bloch & Schneider) which probably acts as postcyclic host. Rhabdochona (Globochona) puntii n. sp. differs markedly from its congeners in the body size, the number and distribution of caudal papillae, in the presence of an unpaired papilla-like structure on the anterior cloacal lip, and in having unusual shape and structure of the terminal crown of mucrons. This is the seventh species of the subgenus Globochona Moravec, 1972 reported from freshwater Indian fishes.     

RV-Typer: A Web Server for Typing of Rhinoviruses Using Alignment-Free Approach

Rhinoviruses (RV) are increasingly being reported to cause mild to severe infections of respiratory tract in humans. RV are antigenically the most diverse species of the genus Enterovirus and family Picornaviridae. There are three species of RV (RV-A, -B and -C), with 80, 32 and 55 serotypes/types, respectively. Antigenic variation is the main limiting factor for development of a cross-protective vaccine against RV.Serotyping of Rhinoviruses is carried out using cross-neutralization assays in cell culture. However, these assays become laborious and time-consuming for the large number of strains. Alternatively, serotyping of RV is carried out by alignment-based phylogeny of both protein and nucleotide sequences of VP1. However, serotyping of RV based on alignment-based phylogeny is a multi-step process, which needs to be repeated every time a new isolate is sequenced. In view of the growing need for serotyping of RV, an alignment-free method based on “return time distribution” (RTD) of amino acid residues in VP1 protein has been developed and implemented in the form of a web server titled RV-Typer. RV-Typer accepts nucleotide or protein sequences as an input and computes return times of di-peptides (k = 2) to assign serotypes. The RV-Typer performs with 100% sensitivity and specificity. It is significantly faster than alignment-based methods. The web server is available at http://bioinfo.net.in/RV-Typer/home.html.     

Synthesis and biological activity of 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents

Inhibition of receptor tyrosine kinase (RTK) signaling pathways is an important area for the development of novel anticancer agents. Numerous multikinase inhibitors (MKIs) have been recently approved for the treatment of cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the principal mediator of tumor angiogenesis. In an effort to develop ATP-competitive VEGFR-2 selective inhibitors the 5-chloro-N⁴-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold was designed. The synthesis of the target compounds involved N-(4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)-2,2-dimethylpropanamide) as a common intermediate. A nucleophilic displacement of the 4-chloro group of the common intermediate by appropriately substituted anilines afforded the target compounds. Biological evaluation indicated that compound 5 is a potent and selective VEGFR-2 inhibitor comparable to sunitinib and semaxinib.     

Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.     

Genotyping of Mumps viruses based on SH gene: Development of a server using alignment-free and alignment-based methods

Mumps is an acute infectious childhood disease caused by mumps virus (MuV), a member of genus Rubu-lavirus, family Paramyxoviridae. Based on the genetic variability in small hydrophobic (SH) genes, currently MuVs have been divided into twelve confirmed genotypes designated as A-L and one proposed genotype, M. Despite successful vaccination program, a few genotypes are observed to co-circulate amongst vaccinated population. Furthermore, lack of cross protection between different genotypes is reported and hence, as a part of epidemiological surveillance, WHO has recommended genotyping of MuV. Currently genotyping is carried out using molecular phylogeny analysis (MPA) of SH genes and no genotyping server is available for MuV. The present study reports development of a genotyping server for the same, which employs three independent methods. The server uses two conventional methods viz., BLAST, MPA and a novel method based on Return Time Distribution (RTD), which is developed in-house. A server for genotyping of mumps virus is developed and made available at http://bioinfo.net.in/muv/homepage.html. RTD-based alignment-free method was initially developed for MPA and is applied for genotyping of MuV for the first time. It is found to have 98.95% of accuracy when measured using leave-one-out cross validation method on reference and test datasets. In addition to RTD, the server also imple-ments BLAST and MPA for genotyping of MuV. All the three methods were found to be highly reliable as evident from consensus predictions. A server for genotyping of MuV, which implements sequence-based bioinformatics approaches is developed and validated using SH gene sequences of known genotypes. This server will be useful for epidemiological surveillance and to monitor the circulation of MuV genotypes within and across geographic areas. This will also facilitate phylodynamics studies of mumps viruses.