Arshad Nuzhat, Hashim Jamshed, Minhas Muhammad Ali, Aslam Javeria, Ashraf Tahira, Hamid Syeda Zehra, Iqbal Tahseen, Javed Shumaila
H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, NED University of Engineering and Technology, Karachi 75270, Pakistan.
H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi 75270, Pakistan.
Bioorg Med Chem Lett. 2018 Oct 15;28(19):3251-3254. doi: 10.1016/j.bmcl.2018.07.045. Epub 2018 Jul 31.
Four series of heterocyclic compounds, namely, tetrahydro-2H-1,3,5-thiadiazine thione derivatives were synthesized in good to excellent yields and were screened for their in vitro antileishmanial activities against Leishmania major (promastigotes). Most of the compounds showed significant antileishmanial activity within the range of IC = 15.48-39.36 μM when compared with standard pentamidine (IC = 14.95 μM). The structure-activity relationship showed that N-3 and N-5 substituents have a key role against leishmanicidal activity. The ester analogues (series B) were found to have a 1.5 to 5-fold reduced activity compared to their acidic counterparts. Cytotoxicity against mammalian mouse fibroblast 3 T3 cells was also evaluated and compared between the acid and its ester analogue. The reduction of antileishmanial activity and loss of toxicity in the newly developed THTT ester derivative indicates that these compounds can be used as a template study for the production of effective antileishmanial ester prodrugs.
合成了四类杂环化合物，即四氢-2H-1,3,5-噻二嗪硫酮衍生物，产率良好至优异，并对其针对硕大利什曼原虫（前鞭毛体）的体外抗利什曼活性进行了筛选。与标准喷他脒（IC = 14.95 μM）相比，大多数化合物在IC = 15.48 - 39.36 μM范围内表现出显著的抗利什曼活性。构效关系表明，N-3和N-5取代基对杀利什曼活性起关键作用。发现酯类似物（B系列）与其酸性对应物相比活性降低了1.5至5倍。还评估了对哺乳动物小鼠成纤维细胞3T3细胞的细胞毒性，并在酸及其酯类似物之间进行了比较。新开发的THTT酯衍生物抗利什曼活性的降低和毒性的丧失表明，这些化合物可作为生产有效抗利什曼酯前药的模板研究。
