Trypanocides

Coulthard for amoebicidal action. Each kind of activity increases to a peak as the series is ascended and then diminishes. In the 0-n-alkyl series the peak is at 0-n-butylharmol for Bacillus typhosus, at 0-n-amyl-harmol for Staphylococcus aureus and at 0-n-nonylharmol for Entamoeba histolytica. In the 0-io-diethylaminoalkyl series the peak for B. typhosus is at 0-to-diethylaminononylharmol. No trypanocidal or anti-malarial action was observed in a selection of the compounds tested. ... 

In a similar way, several studies have been devoted to the study of antiprotozoal activity of catechins occurring in green tea extracts. The trypanocidal... 

The in vivo antitumor and trypanocidal effects of dimeric [Irn2(CH3COO)4(L)ra]° (L = classical organic antimalarial drugs, n= 1, 2) are reported.494 The dimeric complexes are characterized by IR spectroscopy. Further studies of monomeric Ir11 complexes, IrnL2, where L = alkyl or aryl dithiocarbamates and xanthates, reveal no clear relation between antitumor and antitrypanosomal actvities.495 Structure-activity data for the Ir11 complexes is presented. 

The in vitro trypanocidal and antitumor activities of lfr(cot)L], cot = cyclotetraene, derivatives of dithiocarbamates and xanthates, have been investigated.700 The Ir complexes were characterized by IR spectroscopy, and MO calculations (Hiickel) were performed on the ligands. Similar studies were performed on [Ir(nbr)L], nbr = norbornadiene, L = derivatives of alquil and aryl xanthates 701 and also on [Ir2(cod)2L]X2, where L = 2-hydroxystilbamidine, X = C1, N03, C104, BPh4, and [Ir(cod)L2 ]X, where L = benznidazole, R0-2516, nifurtimox, niridazole. The complex [Ir2(cod)2(2-hydroxystilbami-dine)](BPh4)2 showed the highest activity, as studied by optical microscopy of rats kidneys. 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

One of the most compelling targets in the polyamine biosynthesis pathway has been S-adenosylmethionine decarboxylase (SAM-DC). This target was chemically validated with the discovery of trypanocidal activity of MDL-73811 nearly two decades ago. Work to understand the unique kinetics for inhibition of this enzyme in T. brucei has shown that a catalytically... 

T. brucei is unable to synthesize purines de novo and, as such, is dependent upon salvage mechanisms from the host. A number of transporters and enzymes are used by T. brucei to accomplish this task, and inhibition of these targets offers promise for development of trypanocides [39]. This strategy has been validated by demonstration that cordycepin (34), a substrate for T. brucei adenosine kinase (TbAK), which terminates RNA synthesis and parasite growth, can cure stage 2 HAT infections in mice when coadministered with deoxycoformycin (35), an adenosine deaminase inhibitor [40]. 

The nitric oxide donor SIN-1 13 (Section 5.03.12) reacts with 4-nitrophenyl chloroformate to give the N-acylated product that also acts as a potent nitric oxide donor. Further derivatives with trypanocidal activities may be prepared by transesterification with various alcohols <2003JHC943>. 

MI327>, CNS depressant <2001AP263>, trypanocidal <2003JHC943>, and radical scavenging <2004BMC4633> properties. 

As in Part I, the discussion is restricted to monocyclic pyrimidines in which the pyrimidine moiety is an important element of the biologically active molecule. Certain classes of pyrimidines which have not been covered include those with quaternary functions, such as the trypanocidal pyrimidinium salts, and vitamin... 

Various 9-A),]V-diethylaminopropyl-l,2,3,4-tetrahydrocarbazoles have been tested against Chagas disease (American trypanosomiasis), a human tropical parasitic disease. It was found that 8-chloro- and/or 8-methoxy-substituted analogs may have promise as trypanocidal substances (479). 

Ribeiro, A. and Pilo-Veloso, D., Trypanocidal flavonoids from Trixis vauthieri, J. Nat. Prod, 60, 836, 1997. 

Intercalation has been demonstrated with a number of other compounds having a polycyclic aromatic system and groups capable of forming hydrogen bonds. Among such compounds are the antibacterial 9-aminoacridine, the antimalarials mepacrine and chloroquine, the veterinary trypanocide ethidium (246), the thioxanthone lucanthone (247 R = Me) and its more active metabolite hycanthone (247 R = CH20H), which are used in the treatment of schistosomiasis, and the antineoplastic alkaloid ellipticine (248). A number of antibiotics, including the actinomycins, echinomycin and bleomycin, also intercalate. 

The medicinal use of arsenic compounds is now very limited, but some are still used in human trypanosomiasis. The effect of heterocyclic groups in reducing toxicity is well shown in the trypanocide melarsoprol (Mel B) (263), in which the severe toxicity of sodium arsanilate (atoxyl) has been reduced successively by substitution with a triazine residue and incorporation of the arsenic atom in a heterocycle. 

Trichomoniasis. Infection by protozoa usually affecting the genitourinary system. Trypanosomiasis. Infection of the blood of man or animals in tropical countries by protozoa transmitted by blood sucking insects. Examples are African sleeping sickness and Chagas disease. Trypanocide a drug for the treatment of trypanosomiasis. Vasomotor relaxation. Relaxation of the walls of blood vessels. 

Trypanocidal activity of phenanthridine derivatives was discovered in 1938 when phenidium (71) was tested versus T. congolense in mice. Dimidium (72) was quickly found more efficacious when both compounds were introduced for field use. However, for cattle, dimidium (72) is a relatively toxic substance. The discovery that homidium (73) is 10 to 50 times more potent as a trypanocide as well as less toxic to the host led to its introduction and continued use at a dose level of 1 mg kg-1. 

Quinapyramine (74) has a broader spectrum of trypanocidal activity than the phenanthridine drugs and is less toxic. A dose of 4.4 mg kg-1 is curative in cattle infected with T. vivax and T. congolense. 

Many studies on the cationic trypanocides have failed to identify their site(s) of action. A recent proposal is that their activity is due to interaction with biologically active polyamines, e.g. spermine and spermidine (80MI10809). These and other polyamines have significant roles in cell division and macromolecular synthesis. 

Experiments with animals demonstrate that DDTC could be used in conjunction with cisplatin chemotherapy325,326. For instance, pretreatment with DDTC protects against the nephrotoxicity of cisplatin therapy Wysor et al.327 have demonstrated the trypanocidal potential of cisplatin and tetraethylthiuram disulphide, the disulphide of DDTC... 

A-Coupling with diazonium salts occurs fairly readily in phenan-thridium salts bearing an amino group at C-8. Many diazoamino compounds have been so prepared in the search for trypanocides,344-348... 

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