Cytotoxic and anticonvulsant aryloxyaryl Mannich bases and related compounds.
A series of 1-(4-aryloxyphenyl)-3-diethylamino-1-propanone hydrochlorides 3a-3e and related compounds 3f, 3g and 4a-4d were synthesised. In addition, a group of 4-(4-aryloxyphenyl)-3-(4-aryloxyphenylcarbonyl)-1-ethyl-4-piperidinol hydrochlorides 6a-6e were prepared which incorporated most of the structural features of 3a-3e. All of these compounds displayed cytotoxic properties towards murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. A number of these compounds possessed noteworthy potencies towards seven human colon cancer cell lines. Some correlations were noted between the IC(50) values generated in the different screens and the sigma, pi and molar refractivity constants of the aryl substituents as well as with the volumes and solvent accessible surface areas of various basic groups. Molecular modelling of representative compounds revealed structural features, which may have contributed to the varying potencies noted. In general, the compounds in series 6 were well tolerated when administered to mice. Anticonvulsant properties were demonstrated by a number of compounds in the maximal electroshock (MES) screen when administered intraperitoneally to mice while 4c and 6e afforded protection in the MES test when given orally to rats.
College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
Sarvesh C
SC
Vashishtha
Gordon A
GA
Zello
Kurt H
KH
Nienaber
Jan
J
Balzarini
Erik
E
De Clercq
James P
JP
Stables
Jonathan R
JR
Dimmock
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210; D008352:Mannich Bases / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011427:Propiophenones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D008352:Mannich Bases; D011427:Propiophenones