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 IC(50) values ranging from 3 to 10 microM. Their 50% cytotoxic concentrations were often >200 microM to lung fibroblast HEL cell proliferation and between 20 and 35 microM 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 microM. Some of the anti-HCMV compounds also showed activity against HIV-1 and HIV-2. 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.
The benzothiadiazine dioxide (BTD) derivatives are potent nonnucleoside human cytomegalovirus (HCMV) inhibitors. As part of our comprehensive structure−activity relationship study
of these compounds, we have now synthesized N,N- and N,O-dibenzyl derivatives with different
para-substituents (alkyl, phenyl, electron-donating, electron-withdrawing) in the phenyl ring
of the benzyl moieties. The antiviral activity against HCMV (AD-169 strain) was also
experimentally measured showing IC50 values between 2.5 and 50 μM. Comparative molecular
field analysis (CoMFA) was employed to generate a model, based upon 32 diverse BTD
derivatives, to delineate structural and electrostatic features important for enhanced activity
against HCMV. The steric (van der Waals) interactions with the receptor majoritary describes
the variation in antiviral activity among the inhibitors. Finally, the CoMFA model was used
to design two sets of novel BTD derivatives. Synthesis and subsequent anti-HCMV evaluation
of these compounds enabled us to maintain the activity of this new kind of HCMV inhibitors.
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