- Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
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Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
- Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
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- Further insights of selenium-containing analogues of WC-9 against Trypanosoma cruzi
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As a continuation of our project aimed at searching for new chemotherapeutic agents against American trypanosomiasis (Chagas disease), new selenocyanate derivatives were designed, synthesized and biologically evaluated against the clinically more relevant dividing form of Trypanosoma cruzi, the etiologic agent of this illness. In addition, in order to establish the role of each part of the selenocyanate moiety, different derivatives, in which the selenium atom or the cyano group were absent, were conceived, synthesized and biologically evaluated. In addition, in order to study the optimal position of the terminal phenoxy group, new regioisomers of WC-9 were synthesized and evaluated against T. cruzi. Finally, the resolution of a racemic mixture of a very potent conformationally rigid analogue of WC-9 was accomplished and further tested as growth inhibitors of T. cruzi proliferation. The results provide further insight into the role of the selenocyanate group in its antiparasitic activity.
- Chao, María N.,Lorenzo-Ocampo, María V.,Szajnman, Sergio H.,Docampo, Roberto,Rodriguez, Juan B.
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p. 1350 - 1361
(2019/02/25)
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- A Synthesis of acetamidines
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The condensation of primary amine with N,N-dimethylacetamide dimethyl acetal yields amixture of acetamidine and imidate ester. The product distribution in this reaction depends on the temperature, solvent, and structure of the primary amine. It is possible to suppress the formation of imidate ester by performing the reaction in the presence of excess dimethyl amine, yielding acetamidine as the exclusive product. For acetamidines that cannot be purified either by crystallization or distillation, this new method is necessary for the generation of pure acetamidines in good yields.
- Harjani, Jitendra R.,Liang, Chen,Jessop, Philip G.
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experimental part
p. 1683 - 1691
(2011/05/12)
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- Novel cyclic amide derivatives
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Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.
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- Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi
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As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative was previously shown to be an effective and potent agent against T. cruzi proliferation. Several drugs possessing thiocyanate groups proved to be effective growth inhibitors of T. cruzi growth. Among the designed compounds, it is important to point out the extremely potent activity shown by 11, 23, 38, 53, 90, 99, and 117 against the epimastigote forms of the parasite. All of them exhibited IC50 values in the low micromolar range, and these values were comparable with those presented by our lead drug 4 and ketokonazole, a well-known antiparasitic agent. The activity displayed by the nitrogen-containing derivative 90 was very promising with IC50 values of 3.3 μM. Several other thiocyanate derivatives also proved to be very potent inhibitors of the multiplication of T. cruzi epimastigotes, such as compounds 28, 33, 43, 48, 56, 61, 66, 71, 76, and 124. Compound 43 resulted in being a promising drug because it was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was 3-fold more potent than 4, while 11 showed nearly the same activity as our lead drug against intracellular T. cruzi. It was very surprising that the experimental juvenoid 124, although fairly devoid of activity against epimastigotes, was very effective against intracellular amastigotes growing in myoblasts. The rest of the designed compounds showed a broad degree of inhibitory action, from moderately active drugs to drugs almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospectives not only as a lead drug but also to be used for further in vivo studies.
- Elhalem, Eleonora,Bailey, Brian N.,Docampo, Roberto,Ujváry, István,Szajnman, Sergio H.,Rodriguez, Juan B.
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p. 3984 - 3999
(2007/10/03)
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- 2-(1-naphthyloxy)ethylamines with enhanced affinity for human 5-HT(1Dβ) (h5-HT(1B)) serotonin receptors
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Although the β-adrenergic antagonist propanolol (1) binds at rodent 5- HT(1B) serotonin receptors, it displays low affinity (K(i) > 10 000 nM) for its species homologue 5-HT(1DB) (i.e., h5-HT(1B)) receptors. The structure of propanolol was systematically modified in an attempt to enhance its affinity for the latter population of receptors. Removal of the alkyl hydroxyl group, shortening of the O-alkyl chain from three to two methylene groups, and variation of the terminal amine substituent resulted in compounds, such as N- monomethyl-2-(1-naphthyloxy)-ethylamine (11; K(i) = 26 nM), that display significantly higher h5-HT(1B) affinity than propanolol. Compound 11 was shown to bind equally well at human 5-HT(1Dα) (h5-HT(1D) receptors (K(i) = 34 nM) and was further demonstrated to possess h5-HT(1B) agonist character in an adenylate cyclase assay. It would appear that such (aryloxy)alkylamines may represent a novel class of 5-HT(1D) receptor agonists.
- Ismaiel,Dukat,Law,Kamboj,Fan,Lee,Mazzocco,Buekschkens,Teitler,Pierson,Glennon
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p. 4415 - 4419
(2007/10/03)
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