ANTIPICORNAVIRUS ACTIVITY OF TETRAZOLE ANALOGS RELATED TO DISOXARIL

A series of tetrazole analogues of Win 54954, a broad-spectrum antipic ornavirus compound, has been synthesized to address the acid lability of the oxazoline ring of this series of compounds. The results of X-ra y crystallography studies of several members of the oxazoline series b ound to human rhinovirus type IA and 14 have been used to design compo unds in the tetrazole series with a broad spectrum of activity. Compou nd 16b, which has a three-carbon linkage between the isoxazole and phe nyl rings and a propyl chain extending from the isoxazole ring, exhibi ting an MIC80 for 15 rhinovirus serotypes of 0.20 muM as compared to 0 .40 muM for Win 54954. X-ray studies of 16b bound to human rhinovirus- 14 show that the propyl side chain extends into a pore in the binding site with the possibility of hydrophobic interactions with a pocket fo rmed by Leu106 and a portion of Ser107.