Design, Synthesis And Biological Evaluation Of Novel Substituted TTDs As HIV-1 NNRTIs

The human immunodeficiency virus type 1 (HIV-1) is the causative agent of the acquired immunodeficiency syndrome (AIDS). Increase of anti-AIDS drugs and introduction of highly active antiretroviral therapy (HAART) in the mid nineties has led to a significant reduction in morbidity and mortality of AIDS patients, while drug resistance can still emerge even in the face of this multidrug therapy. Therefore, new and improved anti-AIDS drugs with high effective, low toxic, resistance and low price are urgently needed to gain sustained successful treatment of HIV-1-infected patients.The crucial roles of reverse transcriptase (RT) played in the HIV-1 life cycle makes it become one of the important targets of antiviral therapy. There are two categories drugs targeted at HIV RT:(i) nucleoside and nucleotide analogue RT inhibitors (NRTIs/NtRTIs), which compete with the RT substrate by activating to their triphosphate forms and function as terminators of DNA synthesis after incorporation into the primer strand; and (ii) nonnucleoside RT inhibitors (NNRTIs), including the approved drugs nevirapine, delavirdine, efavirenz and Etravirine, which bind at a similar site distal to the active site within RT despite of their wide structural variation. NNRTIs currently in clinical use have a low genetic barrier to resistance and therefore, novel NNRTIs active against drug-resistant mutants selected by current therapies is of paramount importance and urgently needed.More than 50 different classes of NNRTIs have been reported, among whom, substituted 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives (TTDs) is representative one class, which shows promising prospect.Substituted 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives (TTDs) represented a promising class of specific HIV-1 NNRTIs. The lead of these compounds was QM96521 and QM96625 (EC50=0.1μM and SI>1190). There are also several reports indicate that 1,3-disubstituted-2,1,3-benzothiadiazin-4-one 2, 2-dioxides (BTDs) exhibits potent anti-HIV-1 RT activity and acted as a type of novel HIV-1 NNRTIs. Some lead compounds of BTDs, such as compounds 70 and 71, show low concentration against HIV-1 and good selectivities. Based on the general crystal structure of "butter-fly" type of the HIV-1 RT complexed with NNRTIs, TTDs and BTDs are served as lead compounds, and according to the general principle of bioisosteric replacement, we designed and synthesized a series of novel N1,N3-disubstituted-1,5,6,7-tetrahydrocyclopenta[c]-[1,2,6]thiadiazin-4(3h)-one 2,2-dioxide (TCTDs).For the preparation of the newly designed TCTDs, we chose ethyl 2-oxo cyclopentane carboxylate as the starting material. The important intermediate 1,5,6,7-tetrahydrocyclopenta[c]-[1,2,6]thiadiazin-4(3h)-one 2,2-dioxide were prepared by refluxing the starting material and urethane in the presence of p-toluenesulfonic acid, deethoxycarbonylation, acylation, deprotection and ring-closure. Finally, a selectivity alkylating reaction gives the 24 end products (M1-M24). All of their structures were identified by IR, MS and 1H-NMR spectral analysis respectively.The preliminary activity and cytotoxicity screening of the newly designed and synthesized TCTDs derivatives were tested in MT-4 cells for inhibition of HIV-1 (strainⅢB) and HIV-2 (strain ROD).The results were expressed in the form of EC50, CC50and SI (selectivity, given by the CC50/EC50 ratio). The screening results show that these compounds do not exhibit evident inhibition activity of HIV-1, indicating that the spatial structure of 1,5,6,7-tetrahydrocyclopenta[c]-[1,2,6]thiadiazin-4(3H)-one 2,2-dioxide does not satisfy the 'butter-fly' type of RT-NNRTIs.In summary, we successfully designed and synthesis one series of novel compounds TCTDs based on the incorporated construction features of TTDs and BTDs.24 compounds of series of TCTDs has obtained. Through biological evaluation, we do not find compounds exhibiting evident inhibition activity of HIV-1. This is an useful information for the development of TTDs of NNRTIs.