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Molecular orbital study of the ring nitrogen basicity of various dihydrofolate reductase inhibitors
Author(s) -
Ghose Arup K.,
Crippen Gordon M.
Publication year - 1985
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560280302
Subject(s) - cndo/2 , protonation , dihydrofolate reductase , chemistry , ring (chemistry) , molecular orbital , computational chemistry , nitrogen , sulfonyl , molecule , stereochemistry , ion , enzyme , organic chemistry , alkyl
We present molecular orbital ( CNDO /2) calculations on the key fragments of different dihydrofolate reductase inhibitors. Distance geometry analysis, physicochemical parameter dependent QSAR , and molecular shape analysis raised some questions regarding the basicity of the ring nitrogen (N1) in these inhibitors and the effect of the various substituents on the basicity. We show that the ring nitrogen N1 of methotrexate has a considerably higher tendency to be protonated compared to that of folic acid. However, not all 2,4‐diamino inhibitors are equally basic. Even 2‐amino‐4‐hydroxyquinazoline is sufficiently basic to be protonated, but not the 2,4‐diamino‐5‐sulfonyl derivatives. The pyrimidinium ion seems to be highly solvated, since in spite of its high protonation energy it is strongly basic. Triazines were found to be the most basic of all the classes studied.