log P estimation of 1,2-dithiole-3-thiones and 1,2-dithiole-3-ones: a comparison of experimental and calculative approaches.
OBJECTIVE
To estimate experimental log P values of formerly described 5-formyl- and 5-acyl-dithiole-3-thiones (DTT) and -dithiole-3-ones (DTO) and to check the validity of five log P calculation programs via experimental log P for a database of 68 DTT and DTO.


METHODS
Experimental log P values were measured by means of octanol/water partitioning; for determining solute concentrations in water, RP-HPLC with spectrophotometric detection was used. For calculating log P, the fragmental methods ACD/log P, CLOGP, and KOWWIN, the atom-based approach XLOGP, and the whole-molecule approach QLOGP were applied.


RESULTS
Quality of calculations significantly differs depending on the subset under consideration. For database compounds 01-48, comprising alkyl and aryl substitution in 4- and 5-position, the fragmental methods ACD/log P, CLOGP, and KOWWIN perform significantly better than the atom-based approach XLOGP and the whole-molecule method QLOGP. For database compounds 49-68, comprising formyl and acyl substitution in 4- and 5-position, superiority of the whole-molecule method QLOGP over the substructure-based approaches is observed. The strong underestimation of log P for compounds 49-68 probably indicates hidden physicochemical phenomena resulting from the juxtaposition of the acyl and dithiole moieties.


CONCLUSIONS
All calculation methods included in this study need a thorough refinement to adequately cope with particular solvation behavior suspected to prevail in formyl- or acyl-DTT and DTO, which represent a chemical class of high pharmacological interest.
Gargadennec
Sylvain
S
Laboratoire de Chimie Analytique, Upres EA 2231, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Rennes cedex, France.
Burgot
Gwenola
G
Burgot
Jean-Louis
JL
Mannhold
Raimund
R
Rekker
Roelof F
RF
D002151:Calorimetry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D016208:Databases, Factual; D007202:Indicators and Reagents; D000442:Octanols; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013871:Thiones / Q000032:analysis*; D013876:Thiophenes / Q000032:analysis*; D014867:Water
D007202:Indicators and Reagents; D000442:Octanols; D013871:Thiones; D013876:Thiophenes; D014867:Water; C049325:1,2-dithiol-3-thione