Chiral Pyrazolo[4,3-e][1,2,4]triazine Sulfonamides—Their Biological Activity, Lipophilicity, Protein Affinity, and Metabolic Transformations

Zofia Bernat,Zbigniew Karczmarzyk,Mariusz Mojzych,Anna Mieszkowska,Katarzyna Kotwica-Mojzych,Joanna Matysiak,Zofia Mazerska

doi:10.3390/app11062660

Abstract

Referring to our previous laboratory results related to the tyrosinase and urease inhibition by pyrazolo[4,3-e][1,2,4]triazine sulfonamides, we examined here in silico the mechanism of action at the molecular level of the investigated pyrazolotriazine sulfonamides by the molecular docking method. The studied compounds being evaluated for their cytotoxic effect against cancer cell lines (MCF-7, K-562) and for recombinant Abl and CDK2/E kinase inhibitory potency turned out to be inactive in these tests. The pyrazolotriazines were also investigated with respect to their lipophilicity and plasma protein binding using HPLC chromatography in isocratic conditions. The observed small affinity for plasma proteins could be advantageous in the potential in vivo studies. Moreover, the compounds were sensitive to metabolic transformations with phase I enzymes, which led to the hydroxylation and dealkylation products, whereas phase II transformations did not occur.

Highlights

Among 1,2,4-triazines condensed with a five-membered heterocycle, the pyrazolo [4,3-e][1,2,4]triazine system is a novel scaffold and important source for the construction of bioactive molecules
The literature reports show that sulfonamides can act as inhibitors of enzymes such as phosphodiesterase type 5 (PDE5) [7], carbonic anhydrase [8,9], tyrosinase [10,11] or cyclin-dependent kinases (CDKs) [12,13]
The appropriate hydrazone 4 was prepared as a key intermediate for the preparation of 1H-pyrazolo[4,3-e][1,2,4]triazine 5

Summary

Introduction

Among 1,2,4-triazines condensed with a five-membered heterocycle, the pyrazolo [4,3-e][1,2,4]triazine system is a novel scaffold and important source for the construction of bioactive molecules. It has been studied less in comparison with the other fused pyrazolotriazines. Its natural derivatives, such as pseudoiodinine, nostocine A and fluviols A-E, have been indicated in the extracellular metabolites of cyanobacterium of the class Pseudomonas fluorescens var. It has been shown that two isoenzymes of carbonic anhydrase, such as CA IX and CA XII, are clearly associated with significant overexpression in many tumors [17,18], and they are involved in key processes associated with the tumor progression and the response to treatment [19]

Methods

Results

Conclusion