Structure-activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors

This paper describes the structure-activity relationships of a new class of cytomegalovirus DNA polymerase inhibitors having two aryl groups joined by an acyloxyamidine linker. Examination of a series of analogues in which th e terminal groups are varied revealed a very narrow SAR around the 2,4-dich lorophenyl group of the lead compound, but a variety of replacements for th e benzothiazole ring are compatible with activity. The most notable of thes e is the isoxazole ring of compound 78, which provides a 30-fold enhancemen t in potency compared to the lead compound. We also describe the design, sy nthesis and evaluation of 10 analogues in which the acyloxyamidine linker i s modified or replaced by an isosteric group. Structure-activity relationsh ip studies identified the linker -NH2 group as a critical pharmacophoric el ement. Ab initio molecular orbital calculations combined with qualitative e stimates of steric interaction energies suggest that the lowest energy conf ormations of the acyloxyamidine linker are characterized by an extended pla nar C-Ar-C=N-O-C arrangement and either a syn-periplanar or anti-periplanar N-O-C-C-Ar, arrangement. Only the anti-periplanar conformation was observe d in the crystal structures of three acyloxyamidines. The most active of th e linker-modified compounds designed on the basis of these studies is the a midine carbamate 20, which is approximately one-third as potent in the cyto megalovirus DNA polymerase inhibition assay as the comparator acyloxyamidin e 53, The activity of 20 suggests that acyloxyamidines may bind to the cyto megalovirus DNA polymerase via an anti-periplanar conformation similar to t hat observed in the crystal structure of acyloxyamidine 36. (C) 2000 Elsevi er Science Ltd. All rights reserved.