Synthesis and Physico-Chemical Properties in Aqueous Medium of All Possible Isomeric Bromo Analogues of Benzo-1H-Triazole, Potential Inhibitors of Protein Kinases

Abstract

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.

Halogen bonding at the ATP binding site of protein kinases: Preferred geometry and topology of ligand binding

“…Although TBBt, TBBz and K59 have very similar structures (see Figure 2 The foregoing differences in the crystal structures clearly indicate that binding of a halogenated ligand is driven by a balance of electrostatic, hydrophobic, hydrogen-bonding and halogen-bonding interactions, with the electrostatic component being predominant. This is supported by analysis of the structure-activity relations for a series of 4,6,7-tribromobenzotriazole derivatives [26], in which the Br at C(5) of TBBt is replaced by various groups differing in their physicochemical properties, and for another series of nine bromobenzo-1H-triazoles representing all possible patterns of halogenation of the benzene ring [27]. Overall, the hydrophobicity of the monoanionic form of the ligand appeared to be the principal factor governing its inhibitory activity against CK2α [26,28].…”

Branched benzothiadiazole-cored oligomers with terminal carbazoles: Synthesis and fluorescence probing nitroaromatics

“…Compound 9-octyl-3-vinyl-9H-carbazole (3) [14], 4-(bis(4-iodophenyl)amino)benzaldehyde [15], 6-iodo-9-octyl-9H-carbazole-3-carbaldehyde [14], 4-(bis(4-((E)-2-(9-octyl-9H-carbazol-6-yl)vinyl)phenyl)amino)benzaldehyde (6) [16] and 4,7-dibromobenzo [c][1,2,5]thiadiazole [17] were synthesized according to the reported procedures. The Heck reaction between compound 3 and 4-bromobenzaldehyde catalyzed by Pd(OAc) 2 at 110 C for 24 h afforded compound 4 in a yield of 65%, which was transformed into compound 5 through Wittig reaction with methyltriphenylphosphoniumiodine in a yield of 83%.…”

7-Iodo-1H-indole-3-carbonitrile

“…Recently, it was postulated that protein kinase inhibitors may interact with their targets by halogen bonds [15][16][17][18] in addition to other interaction types. Along these lines, we were interested in the title compound 3 as a small core fragment for the development of new protein kinase inhibitors.…”