Modification at the C9 position of the marine natural product isoaaptamine and the impact on HIV-1, mycobacterial, and tumor cell activity

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 24; pp. 8495 - 8505
• Main Authors: Gul, Waseem, Hammond, Nicholas L., Yousaf, Muhammad, Bowling, John J., Schinazi, Raymond F., Wirtz, Susan S., de Castro Andrews, Garcia, Cuevas, Carmen, Hamann, Mark T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.12.2006; Elsevier Science
• Subjects: Aaptos; AIDS-Related Opportunistic Infections - drug therapy; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-cancer leads; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Anti-HIV-1 activity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bacteria - drug effects; Biological and medical sciences; General aspects; General pharmacology; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Isoaaptamine derivatives; Leishmania donovani - drug effects; Leukemia P388 - drug therapy; Malaria - drug therapy; Marine natural products; Medical sciences; Mice; Microbial Sensitivity Tests; Miscellaneous. Antibiotics with multiple activities; Mycobacterium; Mycobacterium intracellulare; Mycobacterium tuberculosis - drug effects; Naphthyridines - chemistry; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Porifera - chemistry; Tumor Cells, Cultured; Anti-cancer leads; Anti-HIV-1 activity; Marine natural products; Isoaaptamine derivatives; Antineoplastic agent; Antimalarial; HIV-1 virus; Modeling; Antimicrobial agent; Benzoic acid derivatives; Marine environment; Antiprotozoal agent; Alkaloid; Chemical compound library; Bacteria; Antiviral; Aromatic compound; Chemical synthesis; Acylate; Tumor cell; Hemisynthesis; Kinetoplastida; Human; Protozoa; Opportunistic infection; Pharmacognosy; Retroviridae; Animal origin; Natural compound; Malignant tumor; Mycobacterium intracellulare; Lentivirus; Biological activity; Virus; Cell line; Treatment; Mycobacteriales; Porifera; Leishmania; Mycobacteriaceae; Parasiticide; Actinomycetes; Sponge; Human immunodeficiency virus; Invertebrata
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.08.042

A series of isoaaptamine analogs were prepared at the C9 position of isoaaptamine ( 2) and were evaluated for their biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. As part of an investigation to generate optimized drug leads from marine natural pharmacophores for the treatment of neoplastic and infectious diseases, a series of novel isoaaptamine analogs were prepared by coupling acyl halides to the C9 position of isoaaptamine ( 2) isolated from the Aaptos sponge. This library of new semisynthetic products was evaluated for biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. Compound 4 showed potent activity against HIV-1 (EC 50 0.47 μg/mL), compound 19 proved to possess remarkable activity against Mycobacterium intracellulare with an IC 50 and MIC value of 0.15 and 0.31 μg/mL, while compounds 4 and 17 possessed anti-leishmanial activity with IC 50 values of 0.1 and 0.4 μg/mL, respectively. Compounds 16 and 17 showed antimalarial activity with EC 50 values of 230 and 240 ng/mL, respectively, and compound 14 exhibited an EC 50 of 0.05 μM against the Leukemia cell line K-562.