Abstract
Based on the molecular modeling analysis against Y181C HIV-1 RT, dipyridodiazepinone derivatives containing an unsubstituted lactam nitrogen and 2-chloro-8-arylthiomethyl were synthesized via an efficient route. Some of them were evaluated for their antiviral activity against HIV-1 RT subtype E and were found to exhibit virustatic activity comparable to some clinically used therapeutic agents.
Highlights
The introduction of antiretroviral therapy results in delayed progression of HIV-1
The majority of existing therapy methods have targeted the viral replication at reverse transcriptase (RT) and protease enzyme [1,2]
A new class of therapeutic agents has focused on inhibiting HIV entry into cells, CD4 binding, coreceptor binding and membrane fusion such as T-20 [5]
Summary
The introduction of antiretroviral therapy results in delayed progression of HIV-1. The majority of existing therapy methods have targeted the viral replication at reverse transcriptase (RT) and protease enzyme [1,2]. Nevirapine (1, Figure 1) [7] monotherapy results in relatively rapid drug resistance due to mutation of the RT enzyme. In an effort to develop a second generation inhibitor with improved activity against mutant RT enzyme, a number of dipyridodiazepinone derivatives have been synthesized and evaluated their activities against HIV-1 RT enzymes [8]. On the basis of a molecular modeling analysis of activity against Y181C HIV-1 RT aimed at modifying the nevirapine structure for higher antiviral activity (Table 1), it was shown that the dipyridodiazepinone derivatives containing unsubstituted lactam nitrogens and a 2-chloro-8-arylthiomethyl (T1 and T2) moiety are effective inhibitors for this mutant enzyme when compared with 68nv, used as reference [9]. The result prompted us to develop an efficient synthetic route to prepare 2-chloro-5,11-dihydro-11-ethyl-8(phenylthio)methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one (T1) and 2-chloro-5,11-dihydro-11ethyl-8-(3-methoxy-phenylthio)methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one (T2) and to evaluate their anti-HIV-1 activity as well as verifying our hypothesis
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