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-bromopyridl)]-thiourea (compound HI-443) was five times more potent tha n trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more pot ent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V10 6A mutation. HI-443 was almost as potent against the NNI-resistant HIV-I st rain A17 with a Y181C mutation as it was against HTLVIIIB. 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 IC, value of 3.3 mu M, whereas the IC50 values of trovirdine, nevirapine, and d elavirdine were all >100 mu M. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral a ctivity against NNI-sensitive, NNI-resistant and multidrug-resistant strain s of HIV-l. (C) 1999 Elsevier Science Ltd. All rights reserved.