SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF ETHYLIMIDAZO[4,5,1-JK][1,4]BENZODIAZEPIN-2(1H)-ONE (TIBO) DERIVATIVES .3.

thylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-ones (TIBO), 1, have bee n shown to significantly inhibit HIV-1 replication in vitro by interfe ring with the virus's reverse transcriptase enzyme. They have also dem onstrated potential clinical efficacy in combating HIV-1, on the basis of a preliminary study. Our prior publications have discussed the dis covery of this series of compounds and reported some preliminary chemi cal and biological studies around N-6 substitutions and 5-membered rin g variations of 1. This manuscript describes our synthetic endeavors a round 4, 5, and 7 mono- and disubstitutions of 1 and discusses related HIV-1 inhibitory structure-activity relationships. On the basis of in hibition of HIV-1's cytopathic effects in MT-4 cells, we found that 5- mono-Me-substituted analogues, the original substitution in the early lead compounds, and 7-mono-Me-substituted analogues of 1 were comparab le as being consistently the most active compounds. Although generally less active, the 4,5,7-unsubstituted, 4-mono-substituted, cis- and tr ans-5,7-di-Me-substituted, and cis-4,5-di-Me-substituted analogues of 1 also exhibited some significant desired activity. The remaining tran s-4,5-di-Me-substituted, cis- and trans-4,7-di-Me-substituted, and all 4,5-, 5,6-, 6,7-, and 7,8-fused disubstituted analogues of 1 possesse d no noticeable desired activity.