Enhancement of Benzothiazoles as Pteridine Reductase‑1 Inhibitors for the Treatment of Trypanosomatidic Infections

2-Amino-benzo­[d]­thiazole was identified as a new
scaffold for the development of improved pteridine reductase-1 (PTR1)
inhibitors and anti-trypanosomatidic agents. Molecular docking and
crystallography guided the design and synthesis of 42 new benzothiazoles.
The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition
and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo­[d]­thiazoles
with improved enzymatic activity (TbPTR1 IC50 = 0.35 μM; LmPTR1 IC50 = 1.9 μM)
and low μM antiparasitic activity against T.
brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity
of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2
and 2.7. The compound library was profiled for early ADME toxicity,
and 2-amino-N-benzylbenzo­[d]­thiazole-6-carboxamide
(4c) was finally identified as a novel potent, safe,
and selective anti-trypanocydal agent (EC50 = 7.0 μM).
Formulation of 4c with hydroxypropyl-β-cyclodextrin
yielded good oral bioavailability, encouraging progression to in vivo
studies.

2-氨基苯并[d]噻唑（2-Amino-benzo[d]thiazole）被鉴定为一种新型骨架，可用于开发优化后的蝶啶还原酶1（PTR1）抑制剂与抗动质体类寄生虫药剂。研究借助分子对接与晶体学技术，指导设计并合成了42种新型苯并噻唑类化合物。随后对这些化合物开展了布氏锥虫（Trypanosoma brucei）与硕大利什曼原虫（Leishmania major）的PTR1抑制活性评估，以及体外抗布氏锥虫、婴儿利什曼原虫（Leishmania infantum）无鞭毛体的活性测试。研究团队发现多款2-氨基苯并[d]噻唑类化合物展现出优化的酶抑制活性（TbPTR1半数抑制浓度IC50=0.35 μM；LmPTR1 IC50=1.9 μM），以及针对布氏锥虫的低微摩尔级抗寄生虫活性。针对TbPTR1活性最强的10种化合物，在与甲氨蝶呤（methotrexate）联合使用抗布氏锥虫的测试中，展现出显著的增效作用，增效指数介于1.2至2.7之间。随后对该化合物库开展了早期ADME（吸收-分布-代谢-排泄）毒性谱分析，最终鉴定出2-氨基-N-苄基苯并[d]噻唑-6-甲酰胺（4c）为一种新型强效、安全且具有选择性的抗锥虫药剂，其半数有效浓度EC50=7.0 μM。将4c与羟丙基-β-环糊精（hydroxypropyl-β-cyclodextrin）配伍后，该制剂展现出良好的口服生物利用度，为后续体内研究奠定了良好基础。