Abstract
The inhibition of acetylcholinesterase by nicotinic acid derivatives presented a strong evidence to the supposition of Bergmann, Wilson and Nachmansohn (1) and Wilson (2) that there exists a basic group in the esteratic site of the cholinesterase.
They supposed that a covalent bond was formed between the carbonyl carbon atom of the inhibitors and the nucleophilic center of the enzyme, e.g. the basic group of the esteratic site, because the order of inhibitory strength of these derivatives is consistent with that of electrophilic character of the carbonyl carbon. Fig. 1 shows the chemical structure of nicotinic acid derivatives they used.
They estimated the order of electrophilic properties of each substituent by the order of Hammett's para sigma constant (3) and also by that of the inductometric polarizability.
There is, however, a question whether it might be quite right to assume a hypothesis that the effect of a substituent adjacent to the carbonyl carbon atom is identical to that of the substituent of the para position in the benzene ring.
Furthermore, Hammett's constant of the diethylamino group seems rather too large as compared with that on the Jaffe's table (see the numerals in the parenthesis in Table 1)(4, 5).
Whether the inductometric effect might be large enough to reverse the former effect or not can not be also easily answered.
For these reasons it is favorably considered to treat this problem more quantitatively from the quantum chemical view point. So the author calculates the magnitude of the electrophilic properties of the carbon atom of nicotinic acid derivatives by the simple LCAOMO method and finds that their order is almost parallel to those of Bergmann et al. With some exceptions some other possibilities are, however, suggested.
