Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-29 DOI:10.1016/j.isci.2025.112537

Deepesh Biswas , Rebecca Kristina Edwin , K. Shiva Kumar , Anwar Alam , Dhiraj Kumar , Sandipan Chakraborty , Gopalakrishnan Bulusu , Farhan Jalees Ahmad , Gautham G. Shenoy , Lakshyaveer Singh , Mansi Agarwal , Fouzia Siraj , Srinivas Oruganti , Parimal Misra , Nasreen Zafar Ehtesham , Manojit Pal , Seyed Ehtesham Hasnain

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Abstract

The search for new anti-tubercular agents is vital for the fight against Mycobacterium tuberculosis, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-d]pyrimidine derivative, was discovered as a potent inhibitor of M.tb chorismate mutase (M.tb-CM) with an IC₅₀ = 3.0 ± 0.2 μM (n = 3) and IC₉₀ = 10 μM. The compound demonstrated efficacy against multi-drug resistant M.tb strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular M.tb in THP-1 macrophages. With favorable pharmacokinetics, moderate stability in vitro, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing M.tb infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug.

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结核分枝杆菌氨基酸生物合成途径抑制剂DRILS-1398作为潜在抗结核药物的早期临床前开发

寻找新的抗结核药物对于抗击结核分枝杆菌至关重要，特别是考虑到耐药菌株的增加。吡唑[4,3-d]嘧啶衍生物DRILS-1398是一种有效的结核分枝杆菌（M.tb） chorismate mutase （M.tb- cm）抑制剂，IC50 = 3.0±0.2 μM (n = 3), IC90 = 10 μM。该化合物对多重耐药结核分枝杆菌（MIC = 4 μg/mL, ~ 10.0 μM）具有抑制THP-1巨噬细胞胞内结核分枝杆菌的作用。DRILS-1398具有良好的药代动力学、适度的体外稳定性和良好的安全性，在小鼠体内，每天口服一次，连续7天，剂量高达500 mg/kg体重/天，无毒性。DRILS-1398及其制剂DRILS-1398(F)均能成功清除小鼠肺和脾脏中的结核分枝杆菌感染。这些发现表明，DRILS-1398是开发一流抗结核药物的有希望的主要候选者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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