N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1.
The thiophene-ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV(IIIB). The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC50 value of 3.3 microM, whereas the IC50 values of trovirdine, nevirapine, and delavirdine were all >100 microM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.
Uckun
F M
FM
Drug Discovery Program, and Department of Virology, Hughes Institute, St. Paul, MN 55113, USA.
Pendergrass
S
S
Maher
D
D
Zhu
D
D
Tuel-Ahlgren
L
L
Mao
C
C
Venkatachalam
T K
TK
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; C403248:HI 443; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013890:Thiourea