Pathogenic fungi are a major causative group for opportunistic infections (OIs). AIDS patients and other immunocompromised individuals are at risk for OIs, which if not treated appropriately, contribute to the mortality associated with their conditions. Several studies have indicated that the majority of HIV-positive patients contract fungal infections throughout the course of their disease. Similar observations have been made regarding the increased frequency of bone marrow and organ transplants, the use of antineoplastic agents, the excessive use of antibiotics, and the prolonged use of corticosteroids among others. In addition, several pathogenic fungi have developed resistance to current drugs. Together these have conspired to spur a need for developing new treatment options for OIs. To aid this effort, this article reviews the biological targets of current and emerging drugs and agents that act through these targets for the treatment of opportunistic fungal infections.
Previous studies have indicated that the δ-carboline (2) ring system derived from the natural product cryptolepine (1) may represent a pharmacophore for anti-infective activity. This paper describes the design and synthesis of a small library of substituted δ-carbolines and the evaluation of the antifungal and antibacterial activities. An evaluation of the anti-bacterial activity of a previously reported library of ring-opened analogs was also conducted to provide an opportunity to test the hypothesis that both group of compounds may have the same biological target. Results indicate that against a selected group of fungal pathogens, substituted δ-carbolinium analogs displayed higher potency and several fold lower cytotoxicity than cryptolepine the parent natural product. Both the δ-carbolinium compounds and their ring-opened analogs, exhibited equally high anti-bacterial activity against the selected pathogens and especially against the gram positive bacteria evaluated.
The compound 1-octen-3-ol is a known attractant of some mosquito species, which has led to the hypothesis that olfactory stimulation by this alkenol may be associated with the following structural elements: a terminal site of unsaturation or high electron density; a structural capability for hydrogen bonding, e.g., -OH, -NH2, NHR, NR2, etc.; a saturated hydrocarbon chain of a certain minimum length; and a certain relative distance between the region of high electron density and the alcohol (or other hydrogen-bonding) functional group. Using this logic, we synthesized 20 alkenol analogs based on the octenol double-bonded carbon skeleton. The attraction of female Aedes albopictus and Culex quinquefasciatus to these analogs was compared with 1-octen-3-ol as a standard in semi-field trials. For both species, collections from Mosquito Magnet-X (MMX) suction traps baited with the alkenol analogs in the absence of carbon dioxide were not significantly different from octenol-only baited traps, with the exception of (Z)-3-hepten-1-ol which collected significantly more Ae. albopictus. In the presence of CO2, most of the collections from traps baited with an alkenol were considerably increased for both species but not different from octenol plus CO2, with the exception of Ae. albopictus where (Z)-3-decen-1-ol, (Z)-4-hexen-1-ol, 7-octen-2-ol, and 8-nonen-3-ol significantly depressed trap catches. Although no clearly identifiable structure-activity relationship could be determined from our collected data, we did find that MMX traps baited with carbon dioxide and 4-penten-2-ol or (E)-2-decen-4-ol significantly enhanced Cx. quinquefasciatus collections up to nearly 3-fold compared with octenol plus carbon dioxide.
Previous studies on the indoloquinoline alkaloid, cryptolepine (2), revealed that it has antiinfective properties among other activities. Using Structure Activity Relationship (SAR) techniques, several ring-opened analogs of cryptolepine (3-phenylaminopyridinium and 3-phenylaminoquinolinium derivatives) were designed to improve the potency and lower the cytotoxicity shown by several of the precursor agents. Results indicate that these ring-opened analogs constitute new anti-infective agents with over a 100-fold potency and several fold lower cytotoxicity than cryptolepine from which they are derived.
Opportunistic infections are devastating to immunocompromised patients. And in especially sub-Saharan Africa where the AIDS epidemic is still raging, the mortality rate was recently as high as 70%. The paucity of anti-opportunistic drugs, the decreasing efficacy and the development of resistance against the azoles and even amphotericin B have stimulated the search for new drugs with new mechanisms of action. In a previous work, we showed that a new chemotype derived from the natural product cryptolepine displayed selective toxicity against opportunistic pathogens with minimal cytotoxicity to normal cells. In this manuscript, we report the design and synthesis of substituted benzylthioquinolinium iodides, evaluated their anti-infective properties and formulated some initial structure-activity relationships around phenyl ring A from the original natural product. The sensitivity of the most potent analog 10l, to selected strains of C. cerevisiae was also evaluated leading to the observation that this scaffold may have a different mode of action from its predecessor, cryptolepine.
Manganese (Mn) is essential for normal physiologic functioning; therefore, deficiencies and excess intake of manganese can result in disease. In humans, prolonged exposure to manganese causes neurotoxicity characterized by Parkinson-like symptoms. Mn2+ has been shown to mediate DNA damage possibly through the generation of reactive oxygen species. In a recent publication, we showed that Mn induced oxidative DNA damage and caused lesions in thymines. This study further investigates the mechanisms by which cells process Mn2+-mediated DNA damage using the yeast S. cerevisiae. The strains most sensitive to Mn2+ were those defective in base excision repair, glutathione synthesis, and superoxide dismutase mutants. Mn2+ caused a dose-dependent increase in the accumulation of mutations using the CAN1 and lys2-10A mutator assays. The spectrum of CAN1 mutants indicates that exposure to Mn results in accumulation of base substitutions and frameshift mutations. The sensitivity of cells to Mn2+ as well as its mutagenic effect was reduced by N-acetylcysteine, glutathione, and Mg2+. These data suggest that Mn2+ causes oxidative DNA damage that requires base excision repair for processing and that Mn interferes with polymerase fidelity. The status of base excision repair may provide a biomarker for the sensitivity of individuals to manganese.
The SWI/SNF chromatin-remodeling complex plays an essential role in several cellular processes including cell proliferation, differentiation, and DNA repair. Loss of normal function of the SWI/SNF complex because of mutations in its subunits correlates with tumorigenesis in humans. For many of these cancers, cytotoxic chemotherapy is the primary, and sometimes the only, therapeutic alternative. Among the antineoplastic agents, anthracyclines are a common treatment option. Although effective, resistance to these agents usually develops and serious dose-related toxicity, namely, chronic cardiotoxicity, limits its use. Previous work from our laboratory showed that a deletion of the SWI/SNF factor SNF2 resulted in hypersensitivity to doxorubicin. We further investigated the contribution of other chromatin remodeling complex components in the response to cytotoxic chemotherapy. Our results indicate that, of the eight SWI/SNF strains tested, snf2, taf14, and swi3 were the most sensitive and displayed distinct sensitivity to different cytotoxic agents, while snf5 displayed resistance. Our experimental results indicate that the SWI/SNF complex plays a critical role in protecting cells from exposure to cytotoxic chemotherapy and other cytotoxic agents. Our findings may prove useful in the development of a strategy aimed at targeting these genes to provide an alternative by hypersensitizing cancer cells to chemotherapeutic agents.
δ-Carbolines and Their Ring-Opened Analogues: Synthesis and Evaluation Against Fungal and Bacterial Opportunisitic Pathogens. -A variety of substituted δ-carbolinium analogues (VIII) (10 examples) of the natural product cryptolepine is designed and synthesized. The δ-carbolinium salts display markedly higher antifungal and antibacterial activities and several-fold lower cytotoxicity than the natural alkaloid. The previously reported ring-opened analogues of (VIII) show antibacterial activities similar to their δ-carbolinium counterparts. -(MAZU, T. K.; ETUKALA, J. R.; JACOB, M. R.; KHAN, S. I.; WALKER, L. A.; ABLORDEPPEY*, S. Y.; Eur. J. Med. Chem. 46 (2011) 6, 2378-2385, http://dx.
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