[Synthesis and investigation of protonation properties and lipophilicity of some new quinazolone-3-carboxylic acid derivatives].
Several new quinazolone-carboxylic acid derivatives as potential NMDA and AMPA receptor antagonists have been synthesized, and the protonation properties and lipophilicity of some representative molecules have also been studied. The protonation macroconstants (logK) of 4(3H)-quinazolone (Q0) and two 2-methyl-4-oxo-3H-quinazoline-3-carboxylic acids (Q1, Q2) were determined by pH-potentiometry. The acid-base chemistry of Q1 and Q2, where protein-bindings take place in an overlapping fashion, was described in terms of protonation microconstants (logk) as well. Microspeciation was carried out by UV-pH titration and deductive method. Microspeciation revealed remarkable differences between the two homologue compounds (Q1 and Q2), namely insertion of a second methylene moiety into the aliphatic acid side-chain reversed the predominantly zwitterion-involved protonation pathway into neutral form-involved one. Lipophilicity of our molecules was described by the octanol-water partition coefficients. The apparent partition coefficients of Q1 and Q2 were determined by shake-flask method and converted into true logP values using the protonation microconstants. The unexpected differences between their true logP values were explained, similarly to the different protonation pathways with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of 10 molecules (Q8-Q17, experimental set) was determined by RP-TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7, determined by shake-flask method) and seven pyrido[1,2a]pyrimidines (PP1-PP7). The obtained logP values proved mostly the expected structure-property relationships. These physico-chemical investigations are pieces of predictive information for the pharmacokinetics of our compounds. These are also discussed in the paper.
Almási
J
J
SOTE Gyógyszerészi Kémiai Intézet, Budapest.
Kökösi
J
J
Takácsné
N K
NK
Vámos
J
J
Noszál
B
B
D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D007202:Indicators and Reagents; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry*; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D002264:Carboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D007202:Indicators and Reagents; D011799:Quinazolines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate