Chlorine antiviral activity

A series of novel 2-amino-6-aryl-9-[2(phosphonomethoxy)ethyl] purine bis (2,2,2-trifluoroethyl) esters (404) has been synthesized by satisfactory regioselec-tive alkylation of 2-amino-6-chloropurine (405) with the bis(tri-fluoroethyl)(2-iodoethoxy)methylphosphonate(406), followed by exchanging the chlorine atom in the resultant intermediate (407) for various substituted and unsubstituted benzenethiols and naphthalenethiols. 6-Phenylthio- and 6-(methoxyphenyl)thio-derivatives showed potent Hepatits B-specific antiviral activity in vitro, and 9[2-(phosphonomethoxy)ethyl] adenine and 9[2-(phosphonomethoxy)ethyl] 2,6-diaminopurine have a broad spectrum of activity against viruses (Scheme 105). ... 

A number of 4 -substituted 2 -deoxyuridine nucleosides have been reported which possess potent antiviral activity, albeit of a lesser magnitude than the corresponding thymidine analogs. 4 -Az-dU, for example, had an ED50 of 0.8 juM and an SI >250 whereas 4 -Az-T had respective values of 0.01 ixM and >800. Chlorination of the 5-position of 4 -Az-dU gave a compound with both increased potency and selectivity. Further exploration of this class of compounds to better define structure-activity relationships appears warranted. 

Fluorination of the 5-position of both ddC and AzddC gave analogs with similar potencies as the parent compounds. Chlorination or bromination at the 5-position of ddC gave inactive compounds, whereas chlorination of AzddC (5-Cl-AzddC) did not significantly alter the antiviral activity but did decrease cytotoxicity somewhat. Similarly, the 5-chloro derivative of 3 -F-ddC (3 -F-5-Cl-ddC) significantly decreased the cytotoxicity exhibited by the parent compound. 

---