Yoshida, K. I. et al. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: Exploration of aromatic substituents. Bioorg. Med. Chem.

Mountain View Pharmaceuticals, Inc., Menlo Park, California, United States
Bioorganic & Medicinal Chemistry (Impact Factor: 2.79). 01/2007; 14(24):8506-18. DOI: 10.1016/j.bmc.2006.08.037
Source: PubMed


A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.

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    • "Pyridopyrimidines and arylpiperazines have also been assayed as EPIs of MDR pumps and major efforts have been performed for their optimization (Nakayama et al., 2004a, b; Yoshida et al., 2006a, b, 2007). Differing to the previously described dipeptide amides, that only impede the action of the antibiotics they compete, pyridopyrimidines increase the susceptibility to all substrates of the efflux pumps, indicating a different mechanism of action (Lomovskaya and Bostian, 2006). "
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    ABSTRACT: Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.
    Frontiers in Microbiology 04/2013; 4:103. DOI:10.3389/fmicb.2013.00103 · 3.99 Impact Factor
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    • "Amongst the family of heterocyclic compounds, the heterocycles with N, S and O atoms have attracted the attention of chemical research due to their wide spectrum of biological activities. Morpholine has its unique position in heterocyclic chemistry, and its derivatives are gaining considerable importance due to diverse biological activities such as antimalarial (Singh et al., 2006), antibacterial (Hirokawa et al., 2009), antimicrobial (Fung et al., 2001; Yoshida et al., 2006), antidepressant (Takeuchi et al., 1997), antiproliferative (Li et al., 2009), hypocholesterolemic (Chrysselis et al., 2000), antileukemic (Szulawska et al., 2007; Jakubowska et al., 2008), antibiotic (Piestrzeniewicz et al., 2004) etc. Similarly, piperazine is also a biodynamic heterosystem, and continues to be a target of interest due to its presence in a number of natural and synthetic drugs. "
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    ABSTRACT: Structurally diverse morpholinyl/piperazinylbenzothiazines have been synthesized in quantitative yields by the reaction of substituted 1,4-benzothiazines with morpholine/N-(2-hydroxyethyl)piperazine. 1,4-Benzothiazines were prepared by the reaction of substituted 2-aminobenzenethiols with β-ketoesters. The structures of the synthesized compounds were confirmed by their analytical and spectroscopic data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species; E. coli and Bacillus cereus. Some of the synthesized compounds have shown significant activity against microorganisms.
    Medicinal Chemistry Research 08/2012; 21(8). DOI:10.1007/s00044-011-9732-z · 1.40 Impact Factor
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    • "The structural activity relationship of these compounds revealed that the modification of these compounds by the addition of various hydrophilic chains had yielded a pyridopyrimidine compound (Fig. 3b) with improved solubility (e.g. morpholine derivative) that showed higher activity through the potentiation of flouroquinolones and β-lactam antibiotics in addition to inhibition of the β-lactam efflux (17, 48, 49). "
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    ABSTRACT: Pseudomonas aeruginosa is an opportunistic human pathogen and one of the leading causes of nosocomial infections worldwide. The difficulty in treatment of pseudomonas infections arises from being multidrug resistant (MDR) and exhibits resistance to most antimicrobial agents due to the expression of different mechanisms overcoming their effects. Of these resistance mechanisms, the active efflux pumps in Pseudomonas aeruginosa that belong to the resistance nodulation division (RND) plays a very important role in extruding the antibiotics outside the bacterial cells providing a protective means against their antibacterial activity. Beside its role against the antimicrobial agents, these pumps can extrude biocides, detergents, and other metabolic inhibitors. It is clear that efflux pumps can be targets for new antimicrobial agents. Peptidomimetic compounds such as phenylalanine arginyl β-naphthylamide (PAβN) have been introduced as efflux pump inhibitors (EPIs); their mechanism of action is through competitive inhibition with antibiotics on the efflux pump resulting in increased intracellular concentration of antibiotic, hence, restoring its antibacterial activity. The advantage of EPIs is the difficulty to develop bacterial resistance against them, but the disadvantage is their toxic property hindering their clinical application. The structure activity relationship of these compounds showed other derivatives from PAβN that are higher in their activity with higher solubility in biological fluids and decreased toxicity level. This raises further questions on how can we compact Pseudomonas infections. Of particular importance, the recent resurgence in the use of older antibiotics such as polymyxins and probably applying stricter control measures in order to prevent their spread in clinical sittings.
    Libyan Journal of Medicine 05/2011; 6. DOI:10.3402/ljm.v6i0.5870 · 1.06 Impact Factor
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