Villar Raquel, Vicente Esther, Solano Beatriz, Pérez-Silanes Silvia, Aldana Ignacio, Maddry Joseph A, Lenaerts Anne J, Franzblau Scott G, Cho Sang-Hyun, Monge Antonio, Goldman Robert C
Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/Irunlarrea s/n, 31080 Pamplona, Spain.
J Antimicrob Chemother. 2008 Sep;62(3):547-54. doi: 10.1093/jac/dkn214. Epub 2008 May 23.
To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB).
Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824.
Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of <or=4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3-5 antitubercular drugs).
Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy.
评估一系列新型喹喔啉1,4 - 二氧化物对结核分枝杆菌的体外活性以及在结核病小鼠模型中的疗效。
对喹喔啉1,4 - 二氧化物的酮和酰胺衍生物进行了体外和体内试验，包括：（i）对耐目前使用的抗结核药物（包括耐多药菌株，即对异烟肼和利福平耐药的耐多药结核病，MDR - TB）的结核分枝杆菌的活性；（ii）对非复制性持续菌（NRP）的活性；（iii）最低杀菌浓度（MBC）；（iv）小鼠的最大耐受剂量、口服生物利用度和体内疗效；以及（v）与另一种生物还原药物PA - 824产生交叉耐药的可能性。
对单耐药结核分枝杆菌测试了10种化合物。总体而言，所有化合物均有活性，其对耐药菌株与非耐药菌株的最低抑菌浓度（MIC）比值≤4.00。一种化合物5在结核病小鼠模型中具有口服活性，具有杀菌作用，对NRP菌有活性，对MDR - TB和耐多药临床分离株（对3 - 5种抗结核药物耐药）也有活性。
喹喔啉1,4 - 二氧化物代表了一类新型的口服活性抗结核药物。它们可能生物还原为活性代谢物，但细菌激活途径与临床试验中的生物还原硝基咪唑PA - 824不同。化合物5具有杀菌作用且对NRP菌有活性，表明在生长和非复制细菌中均发生激活导致细胞死亡。据信NRP菌的存在是抗结核治疗疗程延长的主要因素。如果体外对非复制细菌的杀菌活性能转化为体内情况，喹喔啉1,4 - 二氧化物可能为缩短治疗疗程提供途径。
