Structure-activity relationships in platelet-activating factor (PAF). 10. From PAF antagonism to inhibition of HIV-1 replication

Excessive levels of PAF and cells of macrophage lineage appear to play an i mportant role in neuronal cell injury, inflammatory syndrome, and HIV repli cation in CNS resulting in AIDS dementia complex (ADC). The beneficial effe cts of PAF receptor antagonists are evident and give rise to expected thera peutic strategies for neurotrauma. Piperazine derivatives bearing a "cache- oreilles" (ear-muff) electronic distribution are able to inhibit in vitro P AF effects and, thus, could be used in pathologies where this mediator is i nvolved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infec ted monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate fun ction (compounds 1a-d) is favorable to the antiviral activity; (iii) the li pophilicity of the substituent on the piperazinic cycle seems to be less im portant for the anti-PAF activity than for the antiviral one. Our leading c ompound, PMS 601 (compound la), presents a dual activity with IC50 of 8 and 11 mu M for anti-PAF and anti-HIV activity, respectively, without cytotoxi c events at 1000 mu M in MDM. Although its mode of action is not clearly de fined, these data suggest that PMS 601, which displays no effect on acellul ar reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia.