A quantum chemical study of the 5-aminomethinimino-3-methylisoxazole-4-carboxylic acid phenylamides - A new lead structure in the immunosuppressing agents

In this paper we describe structure-activity relationships of 5-aminomethin -imino-3-methylisoxazole-4-carboxylic acid phenylamide (AMIAP) derivatives in various immunological tests in vivo and in vitro. We found a strong rela tionship between atom charges in the amide group in AMIAP derivatives and t heir activities in the HIR in vitro experiments. In particular, the hydroge n's charge within the amide group is best correlated with the immune activi ty. In general, decrease of the electrostatic potential around the amide gr oups is associated with increase of the immunological activity. The studied derivatives may be divided into two groups based on their struc ture and immunological activity which may be low (compound 1 and 3) or high (compound 2, 4, 5, 7 and 8). That division is associated with the presence of hydrogen at the R' substituent, which plays a key role in the immune ac tivity, or, as in the case of compound 2, with the presence of a ethoxy gro up which is a stronger electron-donor as compared to a C1 group. Studying the effects of the compounds on CIR we found a relationship betwee n atom charges of atoms C5, C6 and chlorine substituent with activity of AM IAP derivatives. In addition, the nitrogen atom (N14) from the isoxazole ri ng has a strong charge versus activity relationship. The change of the chlo rine substituent to an ethoxy one did not have any effect on CIR. Studying the effect of AMIBP derivatives on HIR in vivo we found that atom charges o f atom C6, and connected to it hydrogen H25, correlated with immunological activities. The overall biological activity of AMIAP is also reflected by the HOMO orbi tal.