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The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
Some derivatives had similar in vitro trypanocidal activities to melarsoprol (4) against the bloodstream form (BSF or trypomastigote) of the parasite, with 50% growth-inhibiting concentrations in the submicromolar range. Selected compounds were also evaluated in vivo in rodent models infected with T. brucei brucei and T. brucei rhodesiense. Compound (60) (Figure 15) was able to cure mice infected with T. b. brucei at a dose of 20 mg/kg for 4 days. It was also tested with the more stringent T. b. rhodesiense model STIB 900 using the same treatment schedule, but it cured only one in four infected animals, with a mean survival of 35 days compared to eight days for untreated controls (Baliani et al. 2005, 2009). Structure and in vitro anti-T. brucei activities 5-nitrofuran derivatives.
Melarsoprol
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Melarsoprol is a melaminophenyl-based trivalent organic arsenical introduced as an antitrypanosomal drug for the treatment of human African trypanosomiasis (HAT) in 1949 (Barrett and Gilbert, 2006). Experimental work commenced with arsenical agents for treatment of HAT as early as 1904, with the agent tryparsamide introduced in 1919 (Wery, 1994; Maser et al., 2003). Although this was the first antitrypanosomal agent that crossed the blood–brain barrier, it was only effective against Trypanosoma brucei gambiense, not T. brucei rhodesiense. Unfortunately, widespread resistance reduced the utility of this drug. In 1940, the synthesis of the arsenic compound melarsen oxide led to the successful development of melarsoprol in 1949 (Friedheim, 1949).
Trypanosoma spp.
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
How is the disease managed and prevented?Drugs for trypanosomes are toxic.Melarsoprol is used for late stage African trypanosomiasis but can cause a fatal encephalopathy.For chronic South American trypanosomiasis treatment with benznidazole is probably beneficial in children but of uncertain value in adults.Tsetse fly numbers can be reduced by outdoor insecticide-impregnated traps.Improving housing conditions reduces the population of triatomine bugs, which would otherwise live in cracks in walls or thatched roofs.
Emerging compounds and therapeutic strategies to treat infections from Trypanosoma brucei: an overhaul of the last 5-years patents
Published in Expert Opinion on Therapeutic Patents, 2023
Francesco Melfi, Simone Carradori, Cristina Campestre, Entela Haloci, Alessandra Ammazzalorso, Rossella Grande, Ilaria D’Agostino
Melarsoprol (Figure 1) is used as the first-line treatment for the Tbr infection. Otherwise, diseases caused by Tbg are more efficaciously controlled with eflornithine administration. Melarsoprol is an organic trivalent arsenical prodrug of melaminophenyl-arsine complexed with dimercaptopropanol, a metal-chelating moiety useful to decrease metal-associated toxicity. The active metabolite melarsen oxide, after being internalized by the P2 adenosine/adenine transporter, rapidly reacts with the dithiol form of trypanothione, oxidative and chemical stressors scavenger distinctive for kinetoplastid flagellates [9]. The resulting stable adduct represents a competitive inhibitor of trypanothione reductase (TR), which is the corresponding parasite enzyme of the human glutathione reductase acting in the regulation of the thiol/disulfide pool. The synthetic pathway of trypanothione, containing the polyamine spermidine, is subject to alteration due to Ornithine Decarboxylase (ODC) inhibitors, thereby eflornithine and melarsoprol have been proposed as synergistic agents in order to overcome the resistance due to AQP2 mutations emerging since the 1970s. Another possible mechanism of action is the inhibition of pivotal glycolytic enzymes such as phosphogluconate dehydrogenase and pyruvate kinase [10]. Melarsoprol causes different side effects, with post-treatment reactive encephalopathy being rare but extremely fatal.
Synthesis, anti-bacterial and anti-protozoal activities of amidinobenzimidazole derivatives and their interactions with DNA and RNA
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Andrea Bistrović, Luka Krstulović, Ivana Stolić, Domagoj Drenjančević, Jasminka Talapko, Martin C. Taylor, John M. Kelly, Miroslav Bajić, Silvana Raić-Malić
However, current drugs have problems, such as toxicity, poor efficacy, and increasing resistance by the parasites. Although the precise anti-protozoan mechanisms of action of aromatic diamidines have not been fully elucidated, there is considerable evidence that direct interaction with the pathogen genome is important for activity. Recently, a diamidine containing a 1,2,3-triazole ring as central core was synthesised, which displayed better anti-trypanosomal efficacy than melarsoprol, curing all infected mice54. It was found that incorporation of different hydrophobic aromatic head groups linked to the rest of the molecule by an amidine moiety improved both anti-bacterial activity and affinity to DNA27.
Metal nanoparticles restrict the growth of protozoan parasites
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Oluyomi Stephen Adeyemi, Nthatisi Innocentia Molefe, Oluwakemi Josephine Awakan, Charles Obiora Nwonuma, Omokolade Oluwaseyi Alejolowo, Tomilola Olaolu, Rotdelmwa Filibus Maimako, Keisuke Suganuma, Yongmei Han, Kentaro Kato
Trypanosoma and Toxoplasma are protozoan parasites responsible for diseases that cause significant morbidity, mortality and economic burden, predominantly in developing countries [1–3]. For example, African trypanosomosis is a lethal infectious disease for both humans and livestock; an epidemic of this infection would have a major impact on the economic development of sub-Saharan Africa [4]. The causative agents are hemoflagellated protozoan parasites (i.e. Trypanosoma species), which elicit fatal diseases in African mammalian hosts. The human African trypanosomiasis (HAT, also called sleeping sickness) is caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, whereas bovine Trypanosomosis or nagana is caused by Trypanosoma brucei brucei [5–7]. Trypanosoma infection is fatal if left untreated either in humans or animals. Chemotherapy is a major means of controlling the infection; however, the available treatment options have various shortcomings including limited efficacy, toxicity and the emergence of resistant strains of trypanosomes [2,8]. Melarsoprol, one of the few drugs effective against the second stage of the disease, is reported to cause encephalopathy in 10–15% of patients, and approximately 40% of these cases are fatal [9,10]. These highlight the need for innovative strategies to combat trypanosomosis, which puts the health of more than 60 million people in the sub-Saharan Africa at risk annually [11]. Consequently, the lack of effective anti-Trypanosoma therapies, coupled with unsuccessful attempts at vaccine development due to antigenic variation, has stimulated the search for new chemotherapy for trypanosomosis. Therefore, new candidate drugs against trypanosomosis are urgently needed.