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      Salicylanilide carbamates: Antitubercular agents active against multidrug-resistant Mycobacterium tuberculosis strains

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          Antituberculosis drugs: ten years of research.

          Tuberculosis is today amongst the worldwide health threats. As resistant strains of Mycobacterium tuberculosis have slowly emerged, treatment failure is too often a fact, especially in countries lacking the necessary health care organisation to provide the long and costly treatment adapted to patients. Because of lack of treatment or lack of adapted treatment, at least two million people will die of tuberculosis this year. Due to this concern, this infectious disease was the focus of renewed scientific interest in the last decade. Regimens were optimized and much was learnt on the mechanisms of action of the antituberculosis drugs used. Moreover, the quest for original drugs overcoming some of the problems of current regimens also became the focus of research programmes and many new series of M. tuberculosis growth inhibitors were reported. This review presents the drugs currently used in antituberculosis treatments and the most advanced compounds undergoing clinical trials. We then provide a description of their mechanism of action along with other series of inhibitors known to act on related biochemical targets. This is followed by other inhibitors of M. tuberculosis growth, including recently reported compounds devoid of a reported mechanism of action.
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            Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug.

            SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.
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              New targets and screening approaches in antimicrobial drug discovery.

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                Author and article information

                Journal
                Bioorganic & Medicinal Chemistry
                Bioorganic & Medicinal Chemistry
                Elsevier BV
                09680896
                February 2010
                February 2010
                : 18
                : 3
                : 1054-1061
                Article
                10.1016/j.bmc.2009.12.055
                20060303
                0a077bad-19de-4ac5-b35c-573ab85defcf
                © 2010

                http://www.elsevier.com/tdm/userlicense/1.0/

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