[Synthesis and nNOS inhibitory activity of benzenealkyl isothiourea compounds].
OBJECTIVE
To search for novel compounds with potent nNOS inhibitory activity for the treatment of Alzheimer's disease.


METHODS
The target compounds were obtained by introducing benzenealkyl groups into the structure of isothioureas. nNOS inhibitory activity assays were conducted for the target compounds.


RESULTS
Sixteen benzenealkyl isothiourea compounds (I1-16) were synthesized by three different synthetic methods from benzylamine (1) or (substituted) phenethylamine (2). Compounds I1-6 were synthesized from 1 or 2 by reaction with benzoyl isothiocyanate to form the corresponding benzoylthioureas 3 or 4, followed by hydrolysis with 10% sodium hydroxide solution, then S-alkylation with methyl iodide or ethyl iodide. I7-14 were synthesized from 1 or 2 by reaction with methyl isothiocyanate to form the corresponding 1, 3-disubstituted thioureas 7 or 8 which were S-alkylated with methyl iodide or ethyl iodide. I15 and I16 were synthesized from 2 by reaction with dimethyl cyanodithioimidocarbonate. The structures of compounds I1-16 were confirmed by MS, IR, 1HNMR and elementary analysis. The results of preliminary pharmacological test showed that all compounds possessed nNOS inhibitory activity, among which compounds I8, I12 and I14 had good activity.


CONCLUSIONS
Compounds I8, I12 and I14 showed superior pharmacological profiles to the control compound S-methyl-N-(4-methoxyphenyl) isothiourea. The IC50 values of compounds I8, I12 and I14 inhibiting nNOS were 8.13 x 10(-7) mol.L-1, 1.74 x 10(-7) and 2.23 x 10(-7) mol.L-1 respectively, and it is worth further studying.
Xu
Yun-gen
YG
Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China. xyg@public1.ptt.js.cn
Zhang
Jing-xin
JX
Hua
Wei-yi
WY
Zhu
Dong-ya
DY
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D009419:Nerve Tissue Proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D013890:Thiourea