Sankar Jishnu, Bajpai Manish Kumar, Chauhan Anjali, Maddheshiya Ravi, Sharma Nidhi, Sharma Aditya, Kumar Yashwant, Mahajan Dinesh
Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana 121001, India.
Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
ACS Cent Sci. 2025 Jul 9;11(8):1467-1480. doi: 10.1021/acscentsci.5c00576. eCollection 2025 Aug 27.
Isoniazid (INH), an important first-line drug in tuberculosis (TB) treatment, faces significant challenges primarily due to hepatotoxicity and peripheral neuropathy as major side effects. These adverse effects often lead to poor patient compliance and treatment dropouts. The INH's metabolism is responsible for these adverse effects. INH's reactive terminal -NH group is involved in its undesired metabolic transformations. To address this, we designed and synthesized carbamate-based prodrugs of INH by masking the -NH group to reduce its metabolic activity. Herein, we report our efforts to develop such prodrugs and their impact on metabolism and the pharmacokinetic profile of free INH. The stability, bioconversion, and pharmacokinetic profile with detailed metabolite analysis of these prodrugs were determined in mice. The lead prodrug demonstrated enhanced systemic exposure of free INH (1.5-fold, AUC ≈ 3948 ng·h/mL), reduced formation of undesired metabolites, and prolonged half-life (1.3-fold, ≈ 0.88 h) compared to naive INH. This prodrug approach represents a promising strategy for safer and more effective TB therapy, with the potential for less frequent dosing and improved patient compliance.
异烟肼（INH）是结核病（TB）治疗中的一种重要一线药物，主要由于肝毒性和周围神经病变等主要副作用而面临重大挑战。这些不良反应常常导致患者依从性差和治疗中断。INH的代谢是造成这些不良反应的原因。INH具有反应活性的末端-NH基团参与了其不良的代谢转化。为了解决这一问题，我们通过掩蔽-NH基团来降低其代谢活性，设计并合成了基于氨基甲酸酯的INH前药。在此，我们报告我们开发此类前药的努力及其对游离INH代谢和药代动力学特征的影响。在小鼠中测定了这些前药的稳定性、生物转化以及详细代谢物分析的药代动力学特征。与单纯的INH相比，先导前药显示游离INH的全身暴露增加（1.5倍，AUC≈3948 ng·h/mL），不良代谢物的形成减少，半衰期延长（1.3倍，≈0.88 h）。这种前药方法代表了一种用于更安全、更有效结核病治疗的有前景的策略，具有减少给药频率和提高患者依从性的潜力。
