Synthesis and Evaluation of Cyclic Secondary Amine Substituted Phenyl and Benzyl Nitrofuranyl Amides as Novel Antituberculosis Agents

Abstract

In an ongoing effort to develop new and potent antituberculosis agents, a second generation series of nitrofuranyl amides was synthesized based on the lead compound 5-nitro-furan-2-carboxylic acid 3,4-dimethoxy-benzylamide. The primary design consideration was to improve the solubility and consequently bioavailability of the series by the addition 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 M. 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 lead 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.

Pharmacokinetically-Guided Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents

“…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).…”

Recent Efforts for the Development of Antitubercular Drug Containing Diazine Ring

“…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).…”

“…(54) has shown MIC of 12.5 μg/mL [75]. In continuation, a series of di/trisubstituted pyrazolo [3,4-d]pyrimidines (55,56) were observed no significant anti-TB activity at concentrations up to 6.25 μg/mL. A series of N,S-bis-alkylated thiopyrazolo [3,4-d]pyrimidines, based on sequential S-then N-alkylation, is carried out.…”

“…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].…”

Development of nitroimidazopyrans and nitroimidaoxazoles for tuberculosis chemotherapy

“…A series of nitrofuran derivatives ( Figure 6) have been tested against Mtb H37Rv [39]. One compound in this series has shown excellent minimum inhibitor concentration (MIC) value 0.025 μg/mL, which is comparable to that of the frontline anti-tubercular agents like isoniazid and ethambutol.…”