The application of FTIR spectroscopy to concentrated solutions of tetrolic acid shows, for the first time, a direct relationship between molecular self association in solution and H-bonded motifs in the subsequently crystallised solid phases.

Little is known concerning the precise molecular pathway that links fluid-phase molecules to those in nascent crystal nuclei. In this paper the process of molecular self-assembly has been studied in concentrated solutions using FTIR spectroscopy. Three carboxylic acids, benzoic, tetrolic, and mandelic acids, have been chosen on the basis of their differing crystal chemistries, as reflected in observed hydrogen-bonding motifs. Using the solid-state spectra as a means of unambiguous assignment of carboxyl and hydroxyl vibrations associated with hydrogen bonding, spectroscopic data are reported for solutions as a function of both composition and solvent. In the cases of benzoic acid and tetrolic acid, a link between the growth synthon and the structural synthon is apparent. Mandelic acid, on the other hand, provides a more complex case in which strong solvation effects are evident, leading to the conclusion that significant molecular rearrangement must occur within the developing crystal nuclei.

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399'), (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki' = 11.3-42.8 microM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.