Benzothiadiazine dioxide dibenzyl derivatives as potent human cytomegalovirus inhibitors: synthesis and comparative molecular field analysis.
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 IC(50) values between 2.5 and 50 microM. 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.
Martinez
A
A
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain, and Unidad de Virologia, Servicio de Microbiologia, Hospital "Doce de Octubre", 28041 Madrid, Spain. iqmam06@pinar2.csis.es
Gil
C
C
Abasolo
M I
MI
Castro
A
A
Bruno
A M
AM
Perez
C
C
Prieto
C
C
Otero
J
J
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D001593:Benzyl Compounds; D013829:Thiadiazines