Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-<i>a</i>]pyridine-3-carboxamides as Novel Antitubercular Agents

Tang, Jian; Wang, Bangxing; Wu, Tian Shung; Wan, Junting; Tu, Zhengchao; Njire, Moses; Wan, Baojie; Franzblauc, Scott G.; Zhang, Tianyu; Lu, Xiaoyun; Ding, Ke

doi:10.1021/acsmedchemlett.5b00176

Cited by 86 publications

(79 citation statements)

References 23 publications

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“…17 As summarized in Figure 2, the 4-aryl- N -Boc-piperidine adduct was obtained in good yield using the optimized oxalate coupling conditions. After removal of the Boc group, the secondary amine was subsequently coupled with 4-cyanophenyl bromide using our previously published metallaphoto amination protocol 18 to deliver precursor 46 in excellent yield.…”

mentioning

confidence: 97%

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

2016

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Alkyl oxalates, prepared from their corresponding alcohols, are engaged for the first time as carbon radical fragments in metallaphotoredox catalysis. In this report, we demonstrate that alcohols, native organic functional groups, can be readily activated with simple oxalyl chloride to become radical precursors in a net redox-neutral Csp3–Csp2 cross-coupling with a broad range of aryl halides. This alcohol-activation coupling is successfully applied to the functionalization of a naturally occurring steroid and the expedient synthesis of a medicinally relevant drug lead.

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confidence: 97%

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

2016

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“…The in vitro potency against replicating H37Rv-Mtb, non-replicating H37Rv-Mtb (LORA), toxicity to mammalian cells (VERO) and aqueous solubility were determined for these compounds and a positive control, Q203 ( Table 1). The ITA class showed very similar SAR trends to those observed with very structurally similar imidazo[1,2-a]pyridine-3-carboxamines [9,10,15,17,18] and pyrazolo[1,5-a]pyridine-3-carboxamides [29][30][31]. For instance, the most potent compounds were often the most lipophilic compounds as exemplified by ND-11543 and ND-11564 (clogP of 5.4 and 6.6, respectively) whereas polar compounds like ND-11903 and ND-12015 (clogP of 2.4 and 2.1, respectively) were >100-fold less active by comparison (Table 1).…”

Section: Resultsmentioning

confidence: 53%

“…The IPAs, including Q203 (1, Fig 1), target the electron transport chain, specifically at QcrB, a component of the terminal cytochrome oxidase [16,17]. Various scaffolds have emerged that target QcrB (Fig 1) [ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], two classes, imidazo[2,1-b]thiazole-5-carboxamides (ITAs) (2) [26][27][28] and pyrazolo [1,5-a] pyridine-3-carboxamides (3) [28][29][30][31], bear the greatest structural homology and potency relative to the IPAs (Fig 1). We have disclosed the impressive in vitro properties of various ITAs, including low nanomolar potency against replicating and drug-resistant Mtb strains and low cyctotoxicity [26,27], as exemplified by ND-11543 (2).…”

Section: Introductionmentioning

confidence: 99%

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

et al. 2020

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The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 μM and mono-drug resistant potency ranging from 0.0017 to 7 μM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng�hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.

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“…observed that similar type of compounds having pyrazolo[1,5‐ a ]pyridine moiety ( 197 ), instead of imidazole[1,2‐ a ]pyridine, also possessed anti‐TB activity with MIC values of 11.1 and 5.6 nM against drug‐sensitive M. tuberculosis H37Rv and H37Ra strains (Fig. ) …”

Section: Pyridinesmentioning

confidence: 99%

New structural classes of antituberculosis agents

Kumar

Patel

Jain

2017

Medicinal Research Reviews

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Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold-containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti-TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.

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Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents

Cited by 86 publications

References 23 publications

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

New structural classes of antituberculosis agents

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Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents

Cited by 86 publications

References 23 publications

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3–sp2 Cross-Coupling of Oxalates with Aryl Halides

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3–sp2 Cross-Coupling of Oxalates with Aryl Halides

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

New structural classes of antituberculosis agents

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Product

Resources

About

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides

Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp³–sp² Cross-Coupling of Oxalates with Aryl Halides