The effect of opportunistic infections (OI) on immune-compromised populations has been known for decades, but the recent AIDS epidemic has sparked renewed interest in the development of new anti-OI agents. The mechanism of action of a series of cationic unfused-aromatic anti-OI drugs is believed to involve binding of the drug to AT sequences in the minor groove of DNA. Some new anti-OI drug candidates have been synthesized with fused aromatic ring systems (e.g. carbazoles) that do not resemble the classical paradigm for minor-groove interactions at AT sequences in DNA. To characterize the DNA interactions of these compounds, we have used UV-vis absorbance, fluorescence, kinetic measurements, and circular dichroism in conjunction with NMR spectroscopy to evaluate the structure of the complexes formed between the carbazoles and DNA. Application of these methods to carbazoles substituted at either the 3,6 or 2,7 positions with cationic imidazoline groups gave conclusive, but very surprising, evidence that both compounds bind strongly in the minor groove at AT DNA sequences. NMR and molecular modeling of the complexes formed between the 3,6- and 2,7-carbazoles and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor-groove complex. These results have been used as constraints for molecular modeling calculations to construct models of the minor-groove-carbazole complexes and to draw conclusions regarding the molecular basis for the effects of substituent position on carbazole-DNA affinities. The surprising result is that the 2,7 carbazole binds in AT sequences with hydrogen bonds involving one imidazoline group and the carbazole NH. The 3,6-carbazole compound binds in a more "classical" model that uses both imidazoline groups for H-bonding while the carbazole NH points out of the minor groove. The carbazoles thus form a new type of DNA minor groove complex and their excellent biological activities indicate that a variety of fused-ring minor-groove binding agents should be investigated.
3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity) in vitro. Eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 values) at least 10 times higher than that of furamidine. Eighteen compounds (4-8, 12, 14, 18-22, 25, 26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC50 values less than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.
2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6 μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC50 values below 100 nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC50 = 9 nM, SI > 18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, six compounds caused temporary reductions of parasitemia (≥97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes.
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.
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