Abstract

A second generation of benzothiadiazine dioxide (BTD) derivatives was synthesized employing benzylation reactions mainly. The chlorophenylmethyl BTD derivatives showed activity against human cytomegalovirus (HCMV) with IC50 values ranging from 3 to 10 mu M. Their 50% cytotoxic concentrations were often >200 mu M to lung fibroblast HEL cell proliferation and between 20 and 35 mu M for lymphocyte CME cell growth. When cytotoxicity for cell morphology was considered, the minimum cytotoxic concentration for the different BTD derivatives varied between 5 and 200 mu M Some of the anti-HCMV compounds also showed activity against HIV-1 and HIV-8. The chlorophenylmethyl derivative 21 was active against a variety of HCMV clinical isolates from patients with different clinical manifestations and fully maintained its activity against a ganciclovir-resistant HCMV strain. The dibenzyl BTD derivatives did not inhibit HCMV protease, and preliminary pharmacological experiments revealed that their anti-HCMV action stems from interference with an early stage of the viral replicative cycle.