ABSTRACT
A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of 7g, all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Criptococcus neoformans.
Subject(s)
Anti-Infective Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Indoles/pharmacology , Phthalazines/pharmacology , Anti-Bacterial Agents , Anti-Infective Agents/chemistry , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Cell Division/drug effects , Cryptococcus neoformans/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Indoles/chemistry , Microbial Sensitivity Tests , Phthalazines/chemistry , Tumor Cells, CulturedABSTRACT
A series of 2-triazenothiophene derivatives was prepared and tested to evaluate their biological activity. Two compounds inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. Compound 3c inhibited DNA, RNA and protein synthesis, and was also effective against KB cells resistant to etoposide and vincristine. The compounds were inactive against fungi and bacteria.
Subject(s)
Antineoplastic Agents/pharmacology , Thiophenes/pharmacology , Triazenes/pharmacology , Anti-Bacterial Agents , Anti-HIV Agents/pharmacology , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Bacteria/drug effects , Carcinoma/pathology , Cytopathogenic Effect, Viral/drug effects , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Fungi/drug effects , HIV-1/drug effects , HeLa Cells/drug effects , Humans , KB Cells/drug effects , Leukemia/pathology , Lymphoma/pathology , Melanoma/pathology , Structure-Activity Relationship , Thiophenes/chemical synthesis , Triazenes/chemical synthesis , Tumor Cells, Cultured/drug effectsABSTRACT
Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine 5 were synthesized by diazotization of substituted 2-(2-aminophenyl)indoles followed by an intramolecular coupling reaction of the diazonium group with the indole nitrogen. To obtain the indolobenzotriazine system it was necessary to protect the 3 position of the indole nucleus to avoid cyclization into the indolo[3,2-c]cinnoline system 4. Indolobenzotriazines 5a-g were evaluated in vitro for antitumor activity against a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell lines. Some compounds inhibited the proliferation of T and B cell lines at submicromolar concentrations, whereas their activity against solid tumor cell lines was in the micromolar range. When evaluated for their antifungal potential 5a,d inhibited some of the fungi tested, although at concentrations very close to those inhibiting the proliferation of human cells. On the contrary, all indolobenzotriazines proved fairly potent and selective inhibitors of Streptococcus and Staphylococcus. In particular 5b,c,g were up to 80 times more potent than the reference drug streptomycin and inhibited the growth of the above Gram-positive bacteria at concentrations far lower than those cytotoxic for animal cells.
