1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.

Despite the efficacy of combination chemotherapy with arsenic trioxide (ATO), interferon α (IFN) and zidovudine (AZT) for adult T cell leukemia/lymphoma (ATL), the precise mechanism underlying this combination treatment effect is unknown. In the present study, ATO/IFN/AZT was examined in an ATL leukemic cell line (S1T, non-Tax expressing), a human T-lymphotropic virus 1 (HTLV-1)-infected cell line (MT2, Tax-expressing) and primary ATL cells from patients with acute and chronic ATL. IFN/AZT marginally inhibited MT2 cell proliferation, but substantially inhibited S1T cell proliferation. IFN/AZT increased the cleavage of numerous caspases and PARP in S1T cells, and regulated the signal transducer and activator of transcription 1 and nuclear factor-κB signaling pathway. These effects represent the potential anti-ATL mechanisms of INF/AZT in vitro. In addition, the combination of ATO and IFN/AZT demonstrated synergistic effects on S1T cells. Therefore, the Tax-independent mechanism underlying the anti-ATL effect of ATO must be further elucidated.

Along with the prevalence of drug combination therapies, an increasing number of cases about drug-drug interactions (DDI) have been reported, which has drawn a lot of attention due to the potential toxicity and/or therapeutic failure. Pharmacokinetic interactions based on drug metabolic enzymes should be responsible for a great many of DDI. UDP-glucuronosyltransferases (UGT) as the main phase II metabolic enzymes are involved in the metabolism of many endogenous and exogenous substrates. Herein, we designed and optimized a validated cocktail method for the simultaneous evaluation of drug-mediated inhibition of the main five UGT isoforms using respective specific probe substrates (estradiol for UGT1A1, chenodeoxycholic acid for UGT1A3, serotonin for UGT1A6, propofol for UGT1A9/PROG and zidovudine for UGT2B7/AZTG) in human and rat liver microsomes by liquid chromatography-tandem mass spectrometry (LCMS/MS). Moreover, we investigated the risk of interactions among UGT probe substrates, and validated the cocktail method by known positive inhibitors of UGT isoforms. To minimize the substrates interaction, we developed two cocktail subgroups which were further optimized via exploring the experimental conditions. In particular, the cocktail inhibition assay for rapid assessment of in vitro rat UGTs was firstly reported and the values of Km in the liver microsomes from humans and rats were close to each other in the specific UGT subtype. In conclusion, this study has successfully established the cocktail approach to explore UGT activity, especially for UGT inhibition in a fast and efficient way.