Conformational analysis and the active conformation of N-2-phenylguanine derivatives

A conformational analysis of four N-2-phenyl-(substituted)-guanine (PHG) de rivatives, which are herpes simplex virus thymidine kinase inhibitors (HSV TK), was performed mainly with the semiempirical AM1 method. Nonempirical ( ab initio) HF and MP2 calculations were employed to refine some of the resu lts obtained with the semiempirical method. The two dihedral angles that co nnect the phenyl and the guanine rings were varied for systematic conformat ional search. Four stable conformations were found: C1 (theta(1) = 184 degr ees; theta(2) = 58 degrees); C2(theta(1) = 174 degrees; theta(2) = 127 degr ees); C3(theta(1) = 186 degrees; theta(2) = 233 degrees) and C4(theta(1) = 176 degrees; theta(2) = 303 degrees), in which theta(1) = N1-C2-N11-C1', an d theta(2) = C2-N11-C1'-C2'. The conformation C3 was found to be equivalent to the bioactive conformation proposed in a previous paper. (C) 2000 Elsev ier Science B.V, All rights reserved.