Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-<i>b</i>]oxazoles

Sasaki, Hirofumi; Haraguchi, Yoshikazu; Itotani, Motohiro; Kuroda, Hideaki; Hashizume, Hidetoshi; Tomishige, Tatsuo; Kawasaki, Masanori; Matsumoto, Makoto; Komatsu, Makoto; Tsubouchi, Hidetsugu

doi:10.1021/jm060957y

Cited by 168 publications

(144 citation statements)

References 29 publications

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“…(a) Mechanism of action. OPC-67683 is a mycolic acid biosynthesis inhibitor (137). While isoniazid inhibits the synthesis of all mycolic acid subclasses, OPC-67683 inhibits methoxy and ketomycolic acid synthesis only (91).…”

Section: Ii) Gatifloxacin (A) Mechanism Of Actionmentioning

confidence: 99%

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Boogaard

Kibiki

Kisanga

et al. 2009

Antimicrob Agents Chemother

216

132

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2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...

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Section: Ii) Gatifloxacin (A) Mechanism Of Actionmentioning

confidence: 99%

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Boogaard

Kibiki

Kisanga

et al. 2009

Antimicrob Agents Chemother

216

132

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“…Nitroheterocyclic drugs were synthesized at the University of Dundee as described previously (14,16). VL-2098 was prepared in a single step from 4-(Trifluoromethoxy)phenol and (R)-2-bromo-1-((2-methyloxiran-2-yl)methyl)-4-nitro-1H-imidazole using a modification of the published synthesis of delamanid (OPC-67683) (18). Potassium antimonyl tartrate trihydrate (trivalent antimony) was obtained from Sigma (UK), and SSG was obtained from GSK (UK).…”

mentioning

confidence: 99%

Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

Koniordou

Patterson

Wyllie

et al. 2017

Antimicrob Agents Chemother

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This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.

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“…11) Delamanid inhibits mycolic acid synthesis and has demonstrated potent pre-clinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of M. tuberculosis. 12) Further, delamanid has shown anti-TB activity in patients with drug-sensitive TB 13) and in patients with MDR-TB, and is being specifically developed to treat MDR infections.…”

mentioning

confidence: 99%

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

Shimokawa

Sasahara

Yoda

et al. 2014

Biological & Pharmaceutical Bulletin

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Delamanid is a new drug for the treatment of multidrug-resistant tuberculosis. Individuals who are coinfected with human immunodeficiency virus and Mycobacterium tuberculosis may require treatment with a number of medications that might interact significantly with the CYP enzyme system as inhibitors or inducers. It is therefore important to understand how drugs in development for the treatment of tuberculosis will affect CYP enzyme metabolism. The ability of delamanid to inhibit or induce CYP enzymes was investigated in vitro using human liver microsomes or human hepatocytes. Delamanid (100 µM) had little potential for mechanism-based inactivation on eight CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Delamanid's metabolites were noted to inhibit the metabolism of some CYP isoforms, but these effects were observed only at metabolite concentrations that were well above those observed in human plasma during clinical trials. Delamanid (≤10 µM) did not induce CYP1A2, CYP2C9, and CYP3A4 activities in human hepatocytes, and there were no increases in CYP1A2, CYP2B6, CYP2C9, and CYP3A4 mRNA levels. Taken together, these data suggest that delamanid is unlikely to cause clinically relevant drug-drug interactions when co-administered with products that are metabolized by the CYP enzyme system.

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Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles

Cited by 168 publications

References 29 publications

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

Delamanid Does Not Inhibit or Induce Cytochrome P450 Enzymes <i>in Vitro</i>

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