Symmetrical aryl linked bis-iminothiazolidinones as new chemical entities for the inhibition of monoamine oxidases: Synthesis,in vitro biological evaluation and molecular modelling analysis

The multifactorial nature of Parkinson’s disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives (3a–g and 5a–e) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N′-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature. The bis-iminothiazolidinone compounds were investigated in vitro for their inhibition of monoamine oxidase (MAO-A & MAO-B) enzymes with the aim to identify new and distinct pharmacophores for the treatment of neurodegenerative disorders like Parkinson’s disease. Most of the designed compounds exhibited good inhibitory efficacy against monoamine oxidases. Compound 5a was identified as the most potent inhibitor of MAO-A depicting an IC₅₀ value of 0.001 μM, a 4-fold stronger inhibitory strength compared to standard inhibitor (clorgyline: IC₅₀ = 0.0045 μM). Molecular docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed inhibition towards monoamine oxidases.     

Toward optimal use of biomass as carbon source for chemical bioproduction

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The mechanism of Mycobacterium tuberculosis alkylhydroperoxidase AhpD as defined by mutagenesis,crystallography, and kinetics

AhpD, a protein with two cysteine residues, is required for physiological reduction of the Mycobacterium tuberculosis alkylhydroperoxidase AhpC. AhpD also has an alkylhydroperoxidase activity of its own. The AhpC/AhpD system provides critical antioxidant protection, particularly in the absence of the catalase-peroxidase KatG, which is suppressed in most isoniazid-resistant strains. Based on the crystal structure, we proposed recently a catalytic mechanism for AhpD involving a proton relay in which the Glu118 carboxylate group, via His137 and a water molecule, deprotonates the catalytic residue Cys133 (Nunn, C. M., Djordjevic, S., Hillas, P. J., Nishida, C., and Ortiz de Montellano, P. R. (2002) J. Biol. Chem. 277, 20033-20040). A possible role for His132 in subsequent formation of the Cys133-Cys130 disulfide bond was also noted. To test this proposed mechanism, we have expressed the H137F, H137Q, H132F, H132Q, E118F, E118Q, C133S, and C130S mutants of AhpD, determined the crystal structures of the H137F and H132Q mutants, estimated the pKa values of the cysteine residues, and defined the kinetic properties of the mutant proteins. The collective results strongly support the proposed catalytic mechanism for AhpD.     

The conformational restriction of synthetic peptides, including a malaria peptide, for use as immunogens

A new strategy is advanced for the conformational restriction of peptidyl immunogens. Our approach is to replace putative amide-amide hydrogen bonds with covalent hydrogen-bond mimics. Because on average every other amino acid in a protein engages in this bond, the syntheses of diversely shaped peptides can be contemplated. Synthetic methods for introducing a potential hydrogen-bond mimic into a peptide with alpha-helical potential is reported and the structural consequences are discussed. The replacement of the hydrogen bond with a chemical link will modify as well as shape the peptide. To explore the consequences of these changes, a potential synthetic vaccine for malaria, the repeating tetrapeptide Asn-Pro-Asn-Ala, was conformationally restricted. Antibodies to the shaped malarial peptide showed a strong cross reaction with Plasmodium falciparum sporozoites.     

The use of artemether-lumefantrine for the treatment of uncomplicated Plasmodium vivax malaria

The long-standing dearth of knowledge surrounding Plasmodium vivax, the most widely distributed of the malaria species, merits urgent attention. A growing awareness of the true burden of this parasite and its potential to cause severe disease, and the identification of increasing parasite resistance in many areas of the world to chloroquine, the mainstay of vivax treatment, underscores the need to identify new and effective treatment strategies. Artemisinin-based combination therapies (ACTs) have been widely adopted as first-line treatment for P. falciparum malaria and would offer logistic benefits in areas of co-endemicity. However, while ACTs show high and similar efficacy against the blood stages of P. vivax, neither ACTs nor chloroquine are active against vivax hypnozoites and must be complemented with a full course of primaquine to eradicate dormant vivax hypnozoites and prevent relapses. Artemether-lumefantrine (AL), the most commonly deployed ACT, has shown rapid clearance of P. vivax parasitemia and fever. The relatively short half-life of lumefantrine would appear beneficial in terms of reducing risk of resistance when compared to other ACTs. However, it has a shorter capability to suppress vivax relapses or prevent de novo infections, which generally translates into comparatively lower in vivo short-term measures of efficacy (e.g., day 28 or day 42 uncorrected cure rates). Assuming that the different artemisinin derivatives have equivalent efficacy against vivax, differences between AL and other ACTs may be restricted to the duration of plasma therapeutic levels of the partner drug, a variable of limited clinical relevance, particularly in regions with low vivax transmission rates or in cases where primaquine is added to the regimen to prevent relapses. More rigorous assessment of the use of ACTs in general, and AL in particular, for the treatment of P. vivax infections, either alone or in combination with primaquine, is merited. In the meantime, AL treatment of vivax malaria may be a pragmatic choice for areas with chloroquine-resistant P. vivax, and in co-endemic areas where AL is already used routinely against P. falciparum and parasitological differentiation is not routinely performed or only clinical diagnosis is used.     

Scaling up towards international targets for AIDS, tuberculosis, and malaria: contribution of global fund-supported programs in 2011-2015

Objective

The paper projects the contribution to 2011–2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries.

Design

Estimates, using past trends, for the period 2011–2015 of the number of persons receiving antiretroviral (ARV) treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs) to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation.

Results

Global Fund-supported programs are projected to provide ARV treatment to 5.5–5.8 million people, providing 30%–31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%–63% of the international target for tuberculosis case detection and 30%–35% of the ITN distribution target in sub-Saharan Africa.

Conclusion

Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015.     

Synthesis,pH-dependent,and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem’s short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.     

Mitochondria as targets for detection and treatment of cancer

Mitochondria are dynamic intracellular organelles that play a central role in oxidative metabolism and apoptosis. The recent resurgence of interest in the study of mitochondria has been fuelled in large part by the recognition that genetic and/or metabolic alterations in this organelle are causative or contributing factors in a variety of human diseases including cancer. Several distinct differences between the mitochondria of normal cells and cancer cells have already been observed at the genetic, molecular and biochemical levels. As reviewed in this article, certain of these alterations in mitochondrial structure and function might prove clinically useful either as markers for the early detection of cancer or as unique molecular sites against which novel and selective chemotherapeutic agents might be targeted.     

The non-mevalonate isoprenoid biosynthesis of plants as a test system for new herbicides and drugs against pathogenic bacteria and the malaria parasite

Higher plants and several photosynthetic algae contain the plastidic 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate pathway (DOXP/MEP pathway) for isoprenoid biosynthesis. The first four enzymes and their genes are known of this novel pathway. All of the ca. 10 enzymes of this isoprenoid pathway are potential targets for new classes of herbicides. Since the DOXP/MEP pathway also occurs in several pathogenic bacteria, such as Mycobacterium tuberculosis, and in the malaria parasite Plasmodium falciparum, all inhibitors and potential herbicides of the DOXP/MEP pathway in plants are also potential drugs against pathogenic bacteria and the malaria parasite. Plants with their easily to handle DOXP/MEP-pathway are thus very suitable test-systems also for new drugs against pathogenic bacteria and the malaria parasite as no particular security measures are required. In fact, the antibiotic herbicide fosmidomycin specifically inhibited not only the DOXP reductoisomerase in plants, but also that in bacteria and in the parasite P. falciparum, and cures malaria-infected mice. This is the first successful application of a herbicide of the novel isoprenoid pathway as a possible drug against malaria.     

The use of polyaniline nanofibre as a support for lipase mediated reaction

Highly stable and recoverable polianiline nanofibres are developed for enzyme immobilisation and recovery. Candida rugosa lipase (LP) was immobilised onto a polyaniline nanofibre with cross-linking for enzyme aggregation. The optimal LP loading was 5 mg LP/1 mg polyaniline. The stability of the immobilised LP was measured and shown to be high under vigorous shaking at room temperature. This polyaniline nanofibre LP was easily separable with low-speed centrifugation and repeatedly usable. LP immobilised on polyaniline nanofibre demonstrated high stereoselectivity in the kinetic resolution of racemic (R,S)-ibuprofen and improved the long-term stability as compared to that by the free enzyme, allowing the supported enzyme to be repeatedly used for a series of chiral resolution reactions. The conversion from racemic ibuprofen to a chirally selective compound, a prophilic ester of ibuprofen, was approximately 30% with free LP and approximately 10% with immobilised LP. The enantiomeric excess using immobilised LP after 96 h reaction was 0.884.     

The use of molecular biological methods for the individual characterization of Mycobacterium tuberculosis strains

The expediency of using molecular biological methods for the evaluation of M. tuberculosis clinical strains by individual genetic certification of circulating M. tuberculosis strains has been substantiated. Considerable genetic heterogeneity of M. tuberculosis strains isolated from patients in different regions of the Russian Federation has been established; this heterogeneity is due to the presence of differences in the number of copies (5-26) of element IS6110 in M. tuberculosis cells.     

Measuring the extent and effectiveness of protected areas as an indicator for meeting global biodiversity targets

There are now over 100000 protected areas worldwide, covering over 12% of the Earth's land surface. These areas represent one of the most significant human resource use allocations on the planet. The importance of protected areas is reflected in their widely accepted role as an indicator for global targets and environmental assessments. However, measuring the number and extent of protected areas only provides a unidimensional indicator of political commitment to biodiversity conservation. Data on the geographic location and spatial extent of protected areas will not provide information on a key determinant for meeting global biodiversity targets: 'effectiveness' in conserving biodiversity. Although tools are being devised to assess management effectiveness, there is no globally accepted metric. Nevertheless, the numerical, spatial and geographic attributes of protected areas can be further enhanced by investigation of the biodiversity coverage of these protected areas, using species, habitats or biogeographic classifications. This paper reviews the current global extent of protected areas in terms of geopolitical and habitat coverage, and considers their value as a global indicator of conservation action or response. The paper discusses the role of the World Database on Protected Areas and collection and quality control issues, and identifies areas for improvement, including how conservation effectiveness indicators may be included in the database to improve the value of protected areas data as an indicator for meeting global biodiversity targets.     

Euglena sp. as a suitable source of lipids for potential use as biofuel and sustainable wastewater treatment

Prolific algal growth in sewage ponds with high organic loads in the tropical regions can provide cost-effective and efficient wastewater treatment and biofuel production. This work examines the ability of Euglena sp. growing in wastewater ponds for biofuel production and treatment of wastewater. The algae were isolated from the sewage treatment plants and were tested for their nutrient removal capability. Compared to other algae, Euglena sp. showed faster growth rates with high biomass density at elevated concentrations of ammonium nitrogen (NH₄-N) and organic carbon (C). Profuse growth of these species was observed in untreated wastewaters with a mean specific growth rate (μ) of 0.28 day^?1 and biomass productivities of 132 mg ?L^?1? day^?1. The algae cultured within a short period of 8 days resulted in the 98 % removal of NH₄-N, 93 % of total nitrogen 85 % of ortho-phosphate, 66 % of total phosphate and 92 % total organic carbon. Euglenoids achieved a maximum lipid content of 24.6 % (w/w) with a biomass density of 1.24 g ?L^?1 (dry wt.). Fourier transform infrared spectra showed clear transitions in biochemical compositions with increased lipid/protein ratio at the end of the culture. Gas chromatography and mass spectrometry indicated the presence of high contents of palmitic, linolenic and linoleic acids (46, 23 and 22 %, respectively), adding to the biodiesel quality. Good lipid content (comprised quality fatty acids), efficient nutrient uptake and profuse biomass productivity make the Euglena sp. as a viable source for biofuel production in wastewaters.