Design, Synthesis And Biological Evaluation Of Novel1,2,6-thiadiazine1,1-dioxide Derivatives As HIV-1NNRTIs

HIV-1is the main etiological agent of acquired immunodeficiency syndrome (AIDS), which attacks human immunosystem and causes serve infectious disease. Reverse transcriptase (RT) palys a key role in life cycle of HIV-1, which converts the single-stranded RNA viral genome into a double-stranded linear DNA.As significant and indispensable components of highly active antiretroviral therapy (HAART), non-nucleoside reverse transcriptase inhibitors (NNRTIs) possess the mertits such as high potency, high selectivity and relatively low toxicity. Though HAART helps to effectively control the mobidity and reduce the mortality, anti-HIV therapy is subject in clinical cure for the inevitable emergence of drug resistant viral strains because of the rapid mutations of the residues in RT. So there is an urgent need for developing novel anti-HIV drugs with anti-resistance profile and improved pharmacokinetic property.The NNRTIs with the basic scaffold such as "heterocycle-NH-substituted phenyl", DABO and DAPY have been the hotspot of anti-HIV drug research. They display potency against not only wild virus but also strains with different mutants and have the advantage of high selectivity and excellent pharmacokinetic profile. Especially, two novel drugs which belong to DAPY family have been approved by FDA in2008and2011, respectively.Based on the structural features, binding mode and SAR study of above-mentioned lead NNRTIs, modifications and optimizations of the nucleus and the substituents of the lead are made and novel1,2,6-thiadiazine-1,1-dioxide arylamine derivatives (A series) and novel1,2,6-thiadiazine-1,1-dioxide DABO-DAPY hybrid derivativesare (B series) are designed. According to the bioisosterism of drug design,1,2,6-thiadiazine-1,1-dioxide heterocyclic ring system was introduced in the two series derivatives with an expect to form improved hydrogen bond between the ligand and amino acids of RT, which may led to improved binding affinity with the NNIBP and enhanced potency. In view of the structural flexibility of NNRTIs, a methylene (-CH2-) group was inserted as a linker between the B part and phenoxyl of A series compounds, which might permit the terminal aryl ring to extend farther into the depth of the hydrophobic sub-pocket formed by Tyr181, Tyr188and Trp227in order to develop π-π stack and Van der Waals’ interactions with the amino residues, thus to improve the binding affinity. While B series was designed based on the theory of molecular hybridization, on one hand, preferable group at C-6position of DABO derivatives was retained so that it could form π-π stack and Van der Waals’interactions with hydropobic amino acids such as Tyr181, Tyr188, Trp229and Phe227; on the other hand, substituens that are similar to right wing of DAPY were incorporated so that they located at the solvent interface and enhanced interaction with the amino acids. As a result, A and B series of total451,2,6-thiadiazine-1,1-dioxide derivatives were designed.Computer aided drug design software Sybyl-X1.1was utilized to evaluated the designed compounds. The result indicates that they have the similar binding mode compared with original lead compounds. The significant interaction with key amino acids of NNIBP was kept, and more hydrogen bonds was observed between the newly incorporated thiadiazine ring and amino acids Lys101and Glu138, thus to improve the binding affinity of the designed compounds with RT.For the preparation of the newly designed compouds, different carboxylic acids was chosen as the starting material respectively, which reacted with Meldrum’s acid to produce C-5acetylated Meldrum’s acid. Then1,2,6-thiadiazine-1,1-dioxide heterocyclic ring was obtained by cyclization reaction with sulfonamide. TsCl was used to activate the oxygen of the1,2,6-thiadiazine-1,1-dioxide heterocyclic ring, generating important intermidiate. Finally, NH2of different active substituents attacks the carbon of the important intermidiate to give designed compounds. All of them were identified by MS,1H-and13C-NMR spectral analysis respectively.The bioactivity of designed compounds was evaluated against wild and mutated HIV-1strains in vito in MT-4cells. A series compounds did not show detectable activity against HIV-1in MT-4cells, which may attributed to chemical and physical properties of compounds and complicated mechanism of cell metabolism during activity assay. The bioactivity assay of B series compounds against HIV-1is in progress. While most of B series compounds displayed excellent RT inhibitory activity in the primary anti-RT inhibitory assay, and several compounds were more potent than reference drug NVP (IC50=2.μM), but less potent than ETR (IC50=0.130μM). Especially, the two most potent compounds were Ba9and Bb7, with IC50value of0.270μM and0.397μM, respectively.Taken in sum, based on the structural features, binding mode and SAR study of lead compounds,45compounds were designed by utilization of bioisosterism and molecular hybridization design theory and synthesized, which were identified by MS,1H-and13C-NMR spectral analysis. Despite of the discouraging bioactivity of A series compounds against HIV-1in MT-4cells, it provides reliable and significant information to conduct medicinal chemist to design and optimize more potent anti-HIV drugs.