Benzothiadiazine Dioxide Dibenzyl Derivatives as Potent Human Cytomegalovirus Inhibitors:  Synthesis and Comparative Molecular Field Analysis

Abstract

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.

Preparation of Boronated Heterocyclic Compounds Using Intramolecular Cyclization Reaction

“…Synthesis of N-Aminosulfonyl-o-carboranylmethyl-1,2,3,4-tetrahydroisoquinolines. As an extension of these studies, the reaction of the aminosulfonyl functionalized arylethylamine (13) with o-carboranylacetaldehyde diethyl acetal (4, 5) was investigated in order to evaluate the effect of placing a sulfonyl group on the amine functionality. It has been noted that the sulfamide moiety is widely represented in many natural products and plays an important role in biological activities.…”

“…It has been noted that the sulfamide moiety is widely represented in many natural products and plays an important role in biological activities. 13 The synthesis of the aminosulfonyl tetrahydroisoquinoline skeleton was performed based on the α-sulfamidoalkylation procedure 14 previously reported by us (Scheme 2). The requisite aminosulfonyl functionalized arylamines (13) could be conveniently prepared by aminosulfonylation of the nitrogen atom of 14-17 according to established synthetic protocols.…”

Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine Dioxide Derivatives

“…The model suggested that the steric component is a predominant factor in the antiviral activity of these analogs with electrostatic factors playing a smaller yet significant role [16]. Subsequently, novel series of non-nucleoside anti-HCMV inhibitors were synthesized and showed specific anti-HCMV effects.…”

Synthesis of sufamides of indole series

“…I, II, R 1 = H (a), Me (b); III, R 1 = Me, R 2 = H, R 3 = 1,3-thiazol-2-yl (a); R 1 = R 2 = H: R 3 = 4-FC 6 Compounds containing a fragment N-SO 2 -N exhibit antiviral action [1], inhibit phosphodiesterase [2], are antagonists of dopamine D2 [3] and leucotriene [4].…”