Synthesis and Structure−Activity Studies of Biphenyl Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

Palmer, Brian D.; Thompson, A. M.; Sutherland, Hamish S.; Blaser, Adrian; Kmentová, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.

doi:10.1021/jm901207n

Cited by 105 publications

(178 citation statements)

References 22 publications

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“…19,50 In this assay, both 9 and 44 (100 mg/kg) showed efficacies similar to rifampicin (15 mg/kg), respectively 9.3-and 7.6-fold superior to 4, whereas the S enantiomer of 7 (18) was slightly less efficacious than 4 (at 100 mg/kg; Figure 3). Nevertheless, the VL lead 9 was reportedly much less active than delamanid (5) in a comparable M. tb infection model.…”

Section: Sar Of Nitroimidazooxazoles For Tbmentioning

confidence: 91%

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

et al. 2016

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Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability towards liver microsomes was highly variable.Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.3

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Section: Sar Of Nitroimidazooxazoles For Tbmentioning

confidence: 91%

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

et al. 2016

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“…When novel and experimental compounds were examined, none of the current derivations of the nitroimidazole based compounds (Olaru et al, 2015; Palmer et al, 2010) (delamanid, pretomanid and SN30488) were able to reduce light from the pellicle-grown M. tuberculosis at the concentrations tested (Table 1, Figs. 2H–2J and 3H–3J).…”

Section: Resultsmentioning

confidence: 99%

Effect of common and experimental anti-tuberculosis treatments onMycobacterium tuberculosisgrowing as biofilms

Dalton

Phummarin

et al. 2016

PeerJ

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Much is known regarding the antibiotic susceptibility of planktonic cultures of Mycobacterium tuberculosis, the bacterium responsible for the lung disease tuberculosis (TB). As planktonically-grown M. tuberculosis are unlikely to be entirely representative of the bacterium during infection, we set out to determine how effective a range of anti-mycobacterial treatments were against M. tuberculosis growing as a biofilm, a bacterial phenotype known to be more resistant to antibiotic treatment. Light levels from bioluminescently-labelled M. tuberculosis H37Rv (strain BSG001) were used as a surrogate for bacterial viability, and were monitored before and after one week of treatment. After treatment, biofilms were disrupted, washed and inoculated into fresh broth and plated onto solid media to rescue any surviving bacteria. We found that in this phenotypic state M. tuberculosis was resistant to the majority of the compounds tested. Minimum inhibitory concentrations (MICs) increased by 20-fold to greater than 1,000-fold, underlying the potential of this phenotype to cause significant problems during treatment.

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“…44 Já no trabalho de Meng e colaboradores foram sintetizados os maleatos ou cloridratos de derivados de SQ-109, onde foi observado que a presença de um átomo de flúor ou de uma metoxila no carbono terciário da adamantila vizinha ao nitrogênio do grupo etilenodiamino aumenta a atividade, em especial com o átomo de flúor onde a potência é duplicada (54 e 55 Figura 12). Outras modificações no grupo geranila e adamantila não aumentaram a atividade (56)(57)(58)Figura 12). 45 O esquema 11 mostra um resumo da relação estrutura-atividade para compostos desta série.…”

Section: Figura 11 Resultados Da Avaliação In Vitro Da Sq-109 E Análunclassified

The Medicinal Chemistry of Novel Molecules in Clinical Trials for Tuberculosis Treatment

Branco¹,

Pinto²,

Boechat³

2012

Revista Virtual De Química

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Tuberculosis is a serious public health problem, especially in underdeveloped or developing countries. The first line anti-TB treatment was developed more than 40 years ago. In addition to the development of strains of Mycobacterium tuberculosis resistant to multiple drugs and co-infection with the AIDS virus, has worsened the situation of this disease worldwide. The urgent need for new therapeutic options active against multidrug-resistant strains and concurrently capable to be used with AIDS treatment has led industries, governments and nongovernmental organizations to develop new drugs. This review describes the process of developing new anti-TB drugs and the chemistry of new molecules drug candidates that are in clinical trials for this disease listed in the global portfolio of Stop TB Partnership.Keywords: Tuberculosis; clinical trial; medicinal chemistry; drug design. ResumoA tuberculose é um grave problema de saúde pública, especialmente em países subdesenvolvidos ou em desenvolvimento. O tratamento anti-TB de primeira escolha foi desenvolvido há mais de 40 anos. Isto, aliado ao desenvolvimento de cepas de Mycobacterium tuberculosis resistentes a múltiplos fármacos e a coinfecção com o vírus da AIDS, tem agravado o quadro desta doença em todo o mundo. A urgente necessidade de tratamentos mais efetivos contra cepas multirresistentes e que possam ser utilizados concomitantemente com medicamentos contra a AIDS, tem estimulado as indústrias, governos e organizações não governamentais a buscar novos fármacos. Esta revisão descreve o processo de desenvolvimento de novos fármacos anti-TB e a química medicinal de novas moléculas em fase clínica para esta patologia, listadas no portfólio global da Stop TB Partnership. Palavras-chave:Tuberculose; fase clínica; química medicinal; planejamento.

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Synthesis and Structure−Activity Studies of Biphenyl Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

Cited by 105 publications

References 22 publications

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

Effect of common and experimental anti-tuberculosis treatments onMycobacterium tuberculosisgrowing as biofilms

The Medicinal Chemistry of Novel Molecules in Clinical Trials for Tuberculosis Treatment

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