Synthesis and physico-chemical properties in aqueous medium of all possible isomeric bromo analogues of benzo-1H-triazole, potential inhibitors of protein kinases.
In ongoing studies on the role of the individual bromine atoms of 4,5,6,7-tetrabromobenzotriazole (TBBt) in its relatively selective inhibition of protein kinase CK2α, we have prepared all the possible two mono-, four di-, and two tri-bromobenzotriazoles and determined their physicochemical properties in aqueous medium. They exhibited a general trend of a decrease in solubility with an increase in the number of bromines on the benzene ring, significantly modulated by the pattern of substitution. For a given number of attached bromines, this was directly related to the electronic effects resulting from different sites of substitution, leading to marked variations of pK(a) values for dissociation of the triazole proton. Experimental data (pK(a), solubility) and ab initio calculations demonstrated that hydration of halogenated benzotriazoles is driven by a subtle balance of hydrophobic and polar interactions. The combination of QM-derived free energies for solvation and proton dissociations was found to be a reasonably good predictor of inhibitory activity of halogenated benzotriazoles vs CK2α. Since the pattern of halogenation of the benzene ring of benzotriazole has also been shown to be one of the determinants of inhibitory potency vs some viruses and viral enzymes, the present comprehensive description of their physicochemical properties should prove helpful in efforts to elucidate reaction mechanisms, including possible halogen bonding, and the search for more selective and potent inhibitors.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warszawa, Poland.
Romualda
R
Wąsik
Patrycja
P
Wińska
Jarosław
J
Poznański
David
D
Shugar
D001966:Bromine / Q000737:chemistry; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007536:Isomerism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D014230:Triazoles; D014867:Water; C012771:benzotriazole; D047390:Casein Kinase II; D001966:Bromine