Chapter 1. Synthesis, Physico-Chemical Properties and Antifungal Activity of New Hybrids of Thiazolo[4,5-D] Pyrimidines with (1h-1,2,4) Triazole


S. Blokhina, PhD, A. Sharapova, PhD, and M. Ol’khovich, PhD
G. A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, Ivanovo, Russian Federation

Part of the book: Pyrimidines and their Importance


A new series of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole containing different linker skeletons and substituents (methyl-, methoxy-, chloro- and fluoro-) in the phenyl ring were designed and synthesized as antifungal agents. The chemical structures of the target compounds were characterized by physico-chemical (1H-NMR, LC-MS) methods. The microdilution broth method was used to investigate their antifungal activities. Structure-activity relationship studies indicated that the introduction of piperazine into the linker is crucial to antifungal activity. The final compounds exhibited in vitro antifungal activity against the following filamentous and yeast fungi: C. parapsilosis ATCC 22019, C. albicans ATCC 24433, C. albicans 8R, C. albicans CBS 8837, C. albicans 604M, C. utilis 84, C. tropicalis 3019, C. glabrata 61 L, C. krusei 432M, Cryptococcus neoformans, A. niger 37a, M. canis B-200, T. rubrum 2002 comparable to fluconazole. The amorphous nature of the obtained compounds was verified by DSC and PXRD. The pharmaceutically significant properties of the obtained substances – solubility and lipophilicity – were determined. The kinetic and equilibrium solubilities of the derivatives were studied by the shake-flask method in pharmaceutically relevant solvents: buffer pH 2.0, buffer pH 7.4 and 1-octanol. The solubility of the compounds within the temperature range of (293.15 −313.15) K was found not to exceed 8.6∙10- 4 mol·L-1 in aqueous solvents and 6 10-2 mol·L-1 in alcohol. The solubility values were correlated by the van’t Hoff and modified Apelblat equations. Based on the partition coefficients in the 1-octanol/buffer pH 7.4 system the lipophilicity of the compounds was evaluated. The thermodynamic functions of dissolution and partition for the studied compounds in the selected solvents were calculated. The process of transfer of the compounds from the aqueous phase to the organic one was found to be endothermic and entropy-controlled. The efficiency of some computer programs to predict partition coefficients was tested using experimental data. The in vitro antifungal activity of the studied compounds was shown to increase as their solubility in aqueous solvents became higher.

 Keywords: hybrids, synthesis, solubility, lipophilicity, antifungal activity


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