| Autor: |
Mahajan PS; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Smith SJ; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.; HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Hughes SH; HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Zhao X; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Burke TR Jr; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. |
| Abstrakt: |
An efficient one-pot synthetic method has been developed for the preparation of bicyclic carbamoyl pyridones from the known common intermediate methyl 5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate ( 8 ). The scalable protocol is facile and employs readily available reagents, needing only a single purification as the final step. The utility of the approach was demonstrated by preparing a library of HIV-1 integrase strand transfer inhibitors (INSTIs) that differ by the presence or absence of a double bond in the B-ring of the bicyclic carbamoyl pyridines 6 and 7 . Several of the analogs show good antiviral potencies in single-round HIV-1 replication antiviral assays and show no cytotoxicity in cell culture assays. In general, the compounds with a B-ring double bond have higher antiviral potencies than their saturated congeners. Our methodology should be applicable to the synthesis of a range of new metal-chelating analogs. |
