An insight into tetrahydro-β-carboline–tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents,RSC Medicinal Chemistry

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An insight into tetrahydro-β-carboline–tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-07-21 00:00:00 , DOI: 10.1039/c7md00125h
Pooja Purohit _{1,

2,

3,

4} , Anand Kumar Pandey _{1,

2,

3,

4} , Deepti Singh _{1,

2,

3,

4} , Pradeep Singh Chouhan _{1,

2,

3,

4} , Karthik Ramalingam _{2,

3,

4,

5} , Mahendra Shukla _{2,

4,

6,

7} , Neena Goyal _{2,

3,

4,

5} , Jawahar Lal _{2,

4,

6,

7} , Prem M. S. Chauhan _{1,

2,

3,

4}

Affiliation

A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives (14a–u) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant in vitro activity against the promastigote (IC₅₀ from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC₅₀ from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of L. donovani, and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound 14t was further studied in vivo against the L. donovani/golden hamster model at a dose of 50 mg kg⁻¹ through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound 14t was studied in the golden Syrian hamster, and following a 50 mg kg⁻¹ oral dose, the compound was detected in hamster serum for up to 24 h. It exhibited a large volume of distribution (651.8 L kg⁻¹), high clearance (43.2 L h⁻¹ kg⁻¹) and long mean residence time (10 h).

中文翻译：

对四氢-β-咔啉-四唑杂化物的见解：合成和生物评价作为有效的抗疟药

利用Ugi多组分反应合成了一系列的2,3,4,9-四氢-β-咔啉四唑衍生物（14a–u），并被确定为潜在的无菌化学型。大部分的筛选衍生物表现出显著体外对前鞭毛体的活性（IC ₅₀从0.59±0.35到31±1.27μM）和胞内无鞭毛体形式的（IC ₅₀从1.57±0.12至17.6±0.2μM）的杜氏利什曼原虫，和它们的其活性可与标准药物米非福星和司他葡糖酸钠媲美。最活跃的化合物14吨进行进一步的研究在体内对抗杜氏利什曼原虫/金仓鼠模型以50 mg kg ^-1的剂量通过腹膜内途径连续5天，显示出对脾寄生虫负担的抑制作用为75.04±7.28％。在金色叙利亚仓鼠中研究了化合物14t的药代动力学，口服剂量为50 mg kg ^-1后，在仓鼠血清中检测化合物长达24小时。它表现出大的分布体积（651.8 L kg ^-1），高清除率（43.2 L h ^-1 kg ^-1）和长的平均停留时间（10 h）。

更新日期：2017-09-21

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