Discovery of novel isoxazolines as anti-tuberculosis agents

Tangallapally, Rajendra; Sun, Dianqing; Rakesh,; Budha, Nageshwar; Lee, Robin E. B.; Lenaerts, Anne J.; Meibohm, Bernd; Lee, Richard

doi:10.1016/j.bmcl.2007.09.048

Cited by 89 publications

(51 citation statements)

References 19 publications

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“…A high plasma protein binding reduces the free, pharmacologically active concentrations of a drug and limits its tissue distribution. This might be the major reason why Lee 878 was found to have low in vivo efficacy in a mouse model of M.tb infection despite favorable systemic exposure, high metabolic stability and high in vitro activity (9).…”

Section: Discussionmentioning

confidence: 99%

“…1). Details on the synthesis of the test compounds are described elsewhere (8,9,13). Acetonitrile, HPLC grade water, acetic acid and ammonium acetate were purchased from Fisher Scientific (Pittsburgh, PA).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…In an effort to develop new and more potent therapies to treat TB, a novel class of anti-infectives with high in vitro activity against M.tb, nitrofuranylamides, has recently been characterized by our group (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

Budha

Mehrotra

Tangallapally

et al. 2008

AAPS J

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Abstract. In an effort to develop novel and more potent therapies to treat tuberculosis, a new class of chemical agents, nitrofuranylamides, is being developed. The present study examines biopharmaceutic properties and preclinical pharmacokinetics of nitrofuranylamides at early stages of drug discovery to accelerate the optimization of leads into development candidates. The first tested compound, Lee 562, had high anti-tuberculosis activity in vitro, but exhibited poor metabolic stability resulting in a high systemic clearance, a short elimination half-life and low oral bioavailability in vivo in rats. Thus, two follow-up compounds were designed and tested that included structural modifications for increased metabolic stability. Both compounds showed improved metabolic stability compared to Lee 562, with Lee 878 being much more stable than Lee 952. As a consequence, the oral bioavailability of Lee 878 reached 27% compared to 16% for the other two compounds. This observation prompted us to select compounds based on metabolic stability screening and a new set of nine compounds with high in vitro activity were tested for metabolic stability. The most stable compound in the assay, Lee 1106 was selected for further pharmacokinetic evaluation in rats. Surprisingly, Lee 1106 exhibited poor oral bioavailability, 4.6%. Biopharmaceutic evaluation of the compound showed that the compound has poor aqueous solubility and a high clogP. Based on these results, a screening paradigm was developed for optimization of the nitrofuranylamide lead compounds in a timely and cost-effective manner that might also be applicable to other classes of anti-infective drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Chemicals and Reagentsmentioning

confidence: 99%

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Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

Budha

Mehrotra

Tangallapally

et al. 2008

AAPS J

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“…With the same interest, the efficacy of anti-TB, 5-nitrofuranylamides NFAs (29a-e) against TB complex and other clinically relevant nonmycobacterial species [51] and found that the NFAs were significantly active against Mtb complex [52][53][54][55]. Compound 29a showed preeminent inhibition of MIC 0.006 mg/L against Mtb UT30 (streptomycin resistant at 4 mg/L).…”

Section: Piperazine and Pyrazine Derivativesmentioning

confidence: 96%

“…However, their in-vivo anti-TB activity was limited by high protein binding and low distribution. This led to the discovery of compound 31b as anti-TB agent, which showed 90% inhibition at a concentration of 1.56 μg/mL [52][53][54][55]. A most active molecule 69c has shown a MIC of 0.4 μg/mL against Mtb H37Rv [56].…”

Section: Piperazine and Pyrazine Derivativesmentioning

confidence: 99%

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

Asif¹

2012

Med chem

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There has been considerable interest in the development of new molecule with antibacterial activities particularly against tuberclosis because mycobacterium species have developed resistant against currently used drugs, their toxic effect and long duration of therapy. The diazine (pyridazine, pyrimidine and piperazine) derivatives possess an important class of compound for new drugs research and development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their antitubercular activity. These observations have been guiding for the development of new molecules that possess potent antitubercular activity with minimum side effects or effective against MDR, XDR mycobacterium strains, and also in patient co-infected with HIV/AIDS.

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An Efficient One–pot Procedure for the Direct Preparation of 4,5‐Dihydroisoxazoles from Amides

et al. 2017

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A Mo(CO)6 (molybdenumhexacarbonyl) catalyzed reductive functionalization of amides to afford 5‐amino substituted 4,5‐dihydroisoxazoles is presented. The reduction of amides generates reactive enamines, which upon the addition of hydroximinoyl chlorides and base undergoes a 1,3‐dipolar cycloaddition reaction that gives access to the desired heterocyclic compounds. The transformation of amides is highly chemoselective and tolerates functional groups such as nitro, nitriles, esters, and ketones. Furthermore, a versatile scope of 4,5‐dihydroisoxazoles derived from a variety of hydroximinoyl chlorides and amides is demonstrated.magnified image

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Discovery of novel isoxazolines as anti-tuberculosis agents

Cited by 89 publications

References 19 publications

Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

An Efficient One–pot Procedure for the Direct Preparation of 4,5‐Dihydroisoxazoles from Amides

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