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. 2005 Dec 29;48(26):8261-9.
doi: 10.1021/jm050765n.

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents

Rajendra P Tangallapally  1 , Raghunandan Yendapally, Robin E Lee, Anne J M Lenaerts, Richard E Lee
Affiliations

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents

Rajendra P Tangallapally et al. J Med Chem. .

Abstract

In an ongoing effort to develop new and potent antituberculosis agents, a second-generation series of nitrofuranyl amides was synthesized on the basis of the lead compound 5-nitrofuran-2-carboxylic acid 3,4-dimethoxybenzylamide. The primary design consideration was to improve the solubility and consequently the bioavailability of the series by the addition of hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against Mycobacterium tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study led to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.

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Figures

Figure 1
Figure 1
Target lead compounds and target phenyl and benzyl nitrofuranyl amides.
Scheme 1
Scheme 1
Reagents: Reagents: a) K2CO3, DMSO, 90 °C, 8 h for 6 and 24 h for 7; b1) H2, pd/c, EtOAc-MeOH, room temp., 8 h; b2) For 12c and 12h; SnCl2.2H2O, EtOAc, refluxm 2 h.; c) 11, CH2Cl2, Et3N, room temp.
Scheme 2
Scheme 2
Reagents: a) K2CO3, DMSO, 90 °C, 8 h; b) Red-Al, 0 °C, dry THF, 3 h.; c) 11, CH2Cl2, Et3N, room temp.
Scheme 3
Scheme 3
Reagents: a) K2CO3, DMF, room temp., 7 h; b) Red-Al, 0 °C-room temp., dry THF, 3 h.; c) 11, CH2Cl2, Et3N, room temp.
Scheme 4
Scheme 4
Reagents: a) m-CPBA, NaHCO3, CH2Cl2, room temp., 30 min.
Scheme 5
Scheme 5
Reagents: a) 11, NEt3, CH2Cl2, room temp., 14 h; b) Dess-Martin periodinane, pyridine, CH2Cl2, room temp., 2 h; c) 4-methyl-piperazin-1-yl-amine, ethanol, 1 h reflux, 14 h room temp.
Scheme 6
Scheme 6
Reagents: a) K2CO3, DMSO, 90 °C, 8 h; b) Red-Al, 0 °C-room temp., dry THF, 3 h.; c) 11, CH2Cl2, Et3N, room temp.
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References

    1. Dye C, Scheele S, Dolin P, et al. Global Burden of Tuberculosis-Estimated Incidence, Prevalence, and Mortality by Country. J Am Med Assoc. 1999;2827:677–686. - PubMed

    1. World Health Organization Global Tuberculosis Programme 2005, WHO Report on the Tuberculosis Epidemic 2005, W.H.O. Geneva

    1. de Jong BC, Israelski DM, Corbett EL, Small PMTB. AIDS. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. 2004;55:283–301. - PubMed
    1. Tangallapally RP, Lee RE, Yendapally R, Hevener K, Jones VC, Lenaerts AJM, McNeil MR, Wang Y, Franzblau S, Lee RE. Synthesis amd evaluation of Nitrofuranyl amides as novel inhibitors of UDP-Gal mutase and new antituberculosis agents. J Med Chem. 2004;47:5276–5283. - PubMed
    1. Barry CE, Boshoff HIM, Dowd CS. Prospects for Clinical Introduction of Nitroimidazole Antibiotics for the Treatment of Tuberculosis. Curr Pharm Des. 2004;10:3239–3262. - PubMed

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