Conclusions

Abstract

The author developed efficient methodology for the synthesis of tricyclic heterocycles related to PD 404182 based on the sp²-carbon–heteroatom (O, N, and S) bond formations by C–H functionalization or S_NAr reaction. Starting from arene or haloarene, C–O, C–N, or C–S bonds were formed by simply changing the reactant such as nucleophiles or hetelocumulenes, respectively. These synthetic methods provide powerful approaches for the divergent preparation of pyrimido-benzoxazine, -quinazoline, or -benzo- thiazine derivatives.

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

• 1. The author developed efficient methodology for the synthesis of tricyclic heterocycles related to PD 404182 based on the sp²-carbon–heteroatom (O, N, and S) bond formations by C–H functionalization or S_NAr reaction. Starting from arene or haloarene, C–O, C–N, or C–S bonds were formed by simply changing the reactant such as nucleophiles or hetelocumulenes, respectively. These synthetic methods provide powerful approaches for the divergent preparation of pyrimido-benzoxazine, -quinazoline, or -benzo- thiazine derivatives.

• 2. The author has carried out the intensive SAR studies of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 for the development of anti-HIV agents. The 6-6-6 fused pyrimido[1,2-c][1,3]benzothiazine scaffold and the heteroatom arrangement in PD 404182 considerably contribute to the potent anti-HIV activity. Additionally, through optimization studies of the benzene and cyclic amidine ring parts in PD 404182, threefold more potent inhibitors were obtained compared with the lead compound. The author also revealed by a time of drug addition experiment that PD 404182 derivatives impaired HIV replication at the binding or fusion.

• 3. The author has developed photoaffinity probes with a photoreactive benzophenone moiety and indicator group such as biotin or alkyne for the target identification of PD 404182. By the photolabeling experiment of HIV-1-infected H9 cells using these probes, the author identified proteins specifically bound to PD 404182.

In summary, the author successfully developed novel anti-HIV pyrimidobenzothiazine derivatives. The most potent derivatives exhibited submicromolar inhibitory activity against both HIV-1 and HIV-2. These compounds could be promising agents for anti-HIV therapy because their mechanisms of action through the interaction with several proteins in viruses and/or host cells differ from that of the currently approved anti-HIV agents.