Purohit Pooja, Pandey Anand Kumar, Singh Deepti, Chouhan Pradeep Singh, Ramalingam Karthik, Shukla Mahendra, Goyal Neena, Lal Jawahar, Chauhan Prem M S
Medicinal and Process Chemistry Division , CSIR-Central Drug Research Institute , Lucknow-226031 , U.P. , India . Email:
Division of Biochemistry , CSIR-Central Drug Research Institute , Lucknow-226031 , U.P. , India.
Medchemcomm. 2017 Jul 21;8(9):1824-1834. doi: 10.1039/c7md00125h. eCollection 2017 Sep 1.
A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives () have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant activity against the promastigote (IC from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of , and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound was further studied against the /golden hamster model at a dose of 50 mg kg through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound was studied in the golden Syrian hamster, and following a 50 mg kg 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), high clearance (43.2 L h kg) and long mean residence time (10 h).
利用乌吉多组分反应合成了一系列2,3,4,9-四氢-β-咔啉四唑衍生物（），并将其鉴定为潜在的抗利什曼原虫化学类型。大多数筛选出的衍生物对前鞭毛体（IC为0.59±0.35至31±1.27μM）和细胞内无鞭毛体形式（IC为1.57±0.12至17.6±0.2μM）表现出显著活性，并且它们的活性与标准药物米替福新和葡萄糖酸锑钠相当。对活性最高的化合物以50mg/kg的剂量通过腹腔途径连续5天在/金黄仓鼠模型上进行了进一步研究，其对脾脏寄生虫负荷的抑制率为75.04±7.28%。在金黄叙利亚仓鼠中研究了化合物的药代动力学，口服50mg/kg剂量后，该化合物在仓鼠血清中可检测长达24小时。它表现出较大的分布容积（651.8L/kg）、高清除率（43.2L/h/kg）和较长的平均驻留时间（10小时）。
