Abstract：
Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.
摘要：
人类非洲锥虫病（HAT），由布氏冈比亚锥虫（Tbg）或布氏罗氏锥虫（Tbr）引起的被忽视的热带病，仍然是一个重大的公共卫生问题，超过5500万人面临感染风险。目前的HAT治疗面临着疗效差的挑战，耐药性,和毒性。这项研究提出了针对锥虫物种的氯硝基苯甲酰胺（CNBs）的合成和评估，鉴定先前报道的化合物52是一种有效的和选择性的口服生物可利用的抗锥虫药物。52在体内耐受性良好，并表现出良好的口服药代动力学，在单次口服给药（50mg/kg）后，在啮齿动物中保持血浆浓度超过细胞EC50超过24小时，并达到超过7μM的峰值脑浓度。用52治疗可显着延长感染刚果锥虫和罗氏T.brucei感染的小鼠的寿命。这些结果表明，52是一种强大的抗锥虫药物，具有开发人类和动物非洲锥虫病治疗方法的潜力。
