Compounds for inhibition of HIV infection by blocking HIV entry
A group of compounds that inhibit HIV replication by blocking HIV entry was identified. Two representative compounds, designated NB-2 and NB-64, inhibited HIV replication (p24 production) with IC 50 values <0.5 μg/ml. It was proved that NB-2 and NB-64 are HIV entry inhibitors by targeting the HIV gp41 since: 1) they inhibited HIV-mediated cell fusion; 2) they inhibited HIV replication only when they were added to the cells less than one hour after virus addition; 3) they did not block the gp120-CD4 binding; 4) they did not interact with the coreceptor CXCR4 since they failed to block anti-CXCR4 antibody binding to CXCR4-expressing cells; 5) they blocked the formation of the gp41 core that is detected by sandwich enzyme linked immunosorbent assay (ELISA) using a conformation-specific MAb NC-1; 6) they inhibited the formation of the gp41 six-helix bundle revealed by fluorescence native-polyacrylamide gel electrophoresis (FN-PAGE); and 7) they blocked binding of D-peptide to the hydrophobic cavity within gp41 coiled coil domain, modeled by peptide IQN17. These results suggested that NB-2 and NB-64 may interact with the hydrophobic cavity and block the formation of the fusion-active gp41 coiled coil domain, resulting in inhibition of HIV-1 mediated membrane fusion and virus entry.
1. A method for inhibiting replication of human immunodeficiency virus in cells comprising contacting cells with an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, to inhibit the replication of the human immunodeficiency virus,
wherein X is C;
R 1 is selected from the group consisting of H and methyl;
R 2 is selected from the group consisting of H, methyl and phenyl;
R 3 is selected from the group consisting of H and methyl;
R 4 is selected from the group consisting of H, OH and COCH;
R 5 is selected from the group consisting of H, OH, Cl, COOCH 3 and COOH;
R 6 is selected from the group consisting of H, Cl and COOH;
R 7 is selected from the group consisting of H, OH and methyl;
R 8 is selected from the group consisting of H and CHO;
R 9 is H and at least one of R 4 , R 5 and R 6 is COOH—.
2. The method of claim 1 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
3. A method for treating mammals infected with the human immunodeficiency virus, comprising administering to said mammals an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,
wherein X is C;
R 1 is selected from the group consisting of H and methyl;
R 2 is selected from the group consisting of H, methyl and phenyl;
R 3 is selected from the group consisting of H and methyl;
R 4 is selected from the group consisting of H, OH and COOH;
R 5 is selected from the group consisting of H, OH, Cl, COOCH 3 and COOH;
R 6 is selected from the group consisting of H, Cl and COOH;
R 7 is selected from the group consisting of H, OH and methyl;
R 8 is selected from the group consisting of H and CHO; R 9 is H and at least one of R 4 , R 5 and R 6 is COOH—.
4. The method of claim 3 , further comprising administering to said mammals an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
5. A method for inhibiting replication of human immunodeficiency virus in cells comprising contacting cells with an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, to inhibit the replication of the human immunodeficiency virus,
wherein X is C, R 4 is COON, and one of the following:
(a) R 1 is methyl, R 2 is phenyl, R 5 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(b) R 1 is methyl, R 2 is phenyl, R 5 is Cl, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(c) R 1 is methyl, R 2 is phenyl, and each of R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is H; or
(d) R 1 and R 2 are each methyl, R 5 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(e) R 5 is Cl, and each of R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(f) R 1 and R 2 are each methyl, R 6 is COOH, and each of R 3 , R 5 , R 7 , R 8 and R 9 is H; or
(g) R 1 and R 2 are each methyl, R 7 is OH, and each of R 3 , R 5 , R 6 , R 8 and R 9 is H; or
(h) each of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is H.
6. The method of claim 5 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
7. A method for treating mammals infected with the human immunodeficiency virus, comprising administering to said mammals an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,
wherein X is C, R 4 is COOH, and one of the following:
(a) R 1 is methyl, R 2 is phenyl, R 5 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(b) R 1 is methyl, R 2 is phenyl, R 5 is Cl, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(c) R 1 is methyl, R 2 is phenyl, and each of R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is H; or
(d) R 1 and R 2 are each methyl, R 5 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(e) R 5 is Cl, and each of R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(f) R 1 and R 2 are each methyl, R 6 is COOH, and each of R 3 , R 5 , R 7 , R 8 and R 9 is H; or
(g) R 1 and R 2 are each methyl, R 7 is OH, and each of R 3 , R 5 , R 6 , R 8 and R 9 is H; or
(h) each of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is H.
8. The method of claim 7 , further comprising administering to said mammals an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HTV agents, anti-infective agents, and immunomodulators.
9. A method for inhibiting replication of human immunodeficiency virus in cells comprising contacting cells with an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, to inhibit the replication of the human immunodeficiency virus,
wherein X is C, R 1 and R 2 are each methyl, R 5 is COOH, and one of the following:
(a) R 4 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(b) R 6 is Cl, and each of R 3 , R 4 , R 7 , R 8 and R 9 is H; or
(c) each of R 3 , R 4 , R 6 , R 7 , R 8 and R 9 is H; or
(d) R 6 is Cl, R 8 is CHO, and each of R 3 , R 4 , R 7 and R 9 is H; or
(e) R 7 is OH, and each of R 3 , R 4 , R 6 , R 8 and R 9 is H; or
(f) R 7 is methyl, and each of R 3 , R 4 , R 6 , R 8 and R 9 is H; or
(g) R 8 is CHO, and each of R 3 , R 4 , R 6 , R 7 , and R 9 is H.
10. The method of claim 9 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
11. A method for treating mammals infected with the human immunodeficiency virus, comprising administering to said mammals an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,
wherein X is C, R 1 and R 2 are each methyl, R 5 is COCH, and one of the following:
(a) R 4 is OH, and each of R 3 , R 6 , R 7 , R 8 and R 9 is H; or
(b) R 6 is Cl, and each of R 3 , R 4 , R 7 , R 8 and R 9 is H; or
(c) each of R 3 , R 4 , R 6 , R 7 , R 8 and R 9 is H; or
(d) R 6 is Cl, R 8 is CHO, and each of R 3 , R 4 , R 7 and R 9 is H; or
(e) R 7 is OH, and each of R 3 , R 4 , R 6 , R 8 and R 9 is H; or
(f) R 7 is methyl, and each of R 3 , R 4 , R 6 , R 8 and R 9 is H; or
(g) R 8 is CHO, and each of R 3 , R 4 , R 6 , R 7 and R 9 is H.
12. The method of claim 11 , further comprising administering to said mammals an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
13. A method for inhibiting replication of human immunodeficiency virus in cells comprising contacting cells with an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, to inhibit the replication of the human immunodeficiency virus,
wherein X is C, R 6 is COOH, and one of the following:
(a) R 1 , R 2 and R 7 are each methyl, and each of R 3 , R 4 , R 5 , R 8 and R 9 is H; or
(b) R 1 and R 2 are each methyl, and each of R 3 , R 4 , R 5 , R 7 , R 8 and R 9 is H; or
(c) R 7 is methyl, and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 is H; or
(d) R 1 and R 2 are each methyl, R 5 is Cl, and each of R 3 , R 4 , R 7 , R 8 and R 9 is H; or
(e) R 1 , R 2 and R 3 are each methyl, and each of R 4 , R 5 , R 7 , R 8 and R 9 is H.
14. The method of claim 13 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
15. A method for treating mammals infected with the human immunodeficiency virus, comprising administering to said mammals an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,
wherein X is C, R 6 is COCH, and one of the following:
(a) R 1 , R 2 and R 7 are each methyl, and each of R 3 , R 4 , R 5 , R 8 and R 9 is H; or
(b) R 1 and R 2 are each methyl, and each of R 3 , R 4 , R 5 , R 7 , R 8 and R 9 is H; or
(c) R 7 is methyl, and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 is H; or
(d) R 1 and R 2 are each methyl, R 5 is Cl, and each of R 3 , R 4 , R 7 , R 8 and R 9 is H; or
(e) R 1 , R 2 and R 3 are each methyl, and each of R 4 , R 5 , R 7 , R 8 and R 9 is H.
16. The method of claim 15 , further comprising administering to said mammals an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
17. A compound of the formula I, or a pharmaceutically acceptable salt thereof,
wherein X is C; R 1 and R 2 are CH 3 ; R 3 is H; R 4 is OH; R 5 is COOH; and R 6 , R 7 , R 8 and R 9 are each H.
18. A pharmaceutical composition comprising an effective amount of the compound of claim 17 .
19. A method for inhibiting replication of human immunodeficiency virus in cells, comprising contacting the cells with the pharmaceutical composition of claim 18 .
20. The method of claim 19 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
21. A method for treating mammals infected with the human immunodeficiency virus, or treatment of Acquired Immunodeficiency Syndrome (AIDS) in a subject, comprising administering to said mammals or subject the pharmaceutical composition of claim 18 .
22. The method of claim 21 , further comprising administering to said mammals or subject an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
23. A method for inhibiting replication of human immunodeficiency virus in cells comprising contacting cells with an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, to inhibit the replication of the human immunodeficiency virus,
wherein X is C; R 1 , R 2 and R 3 are each H; R 4 is COOH; R 5 is Cl; and R 6 , R 7 , R 8 and R 9 are each H.
24. The method of claim 23 , further comprising contacting cells with an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.
25. A method for treating mammals infected with the human immunodeficiency virus, comprising administering to said mammals an effective amount of a compound of the formula I, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,
wherein X is C; R 1 , R 2 and R 3 are each H; R 4 is COCH; R 5 is Cl; and R 6 , R 7 , R 8 and R 9 are each H.
26. The method of claim 25 , further comprising administering to said mammals an effective amount of an Acquired Immunodeficiency Syndrome (AIDS) treatment agent selected from the group consisting of anti-HIV agents, anti-infective agents, and immunomodulators.