RESUMEN
BACKGROUND: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated with this disease. METHODS: Herein, the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives have been reported. RESULTS: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effects were evaluated against trypomastigote and amastigote, forming M. tuberculosis activity towards H37Rv sensitive strain and resistant strains. DISCUSSION: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 µM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'- (3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. CONCLUSION: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.
Asunto(s)
Cumarinas/química , Hidrazonas/síntesis química , Hidrazonas/farmacología , Nitrógeno/química , Trypanosoma/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Técnicas de Química Sintética , Farmacorresistencia Bacteriana/efectos de los fármacos , Hidrazonas/química , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC50 values ranging from 3 to 226⯵M, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Tiadiazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/parasitología , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/química , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
BACKGROUND: Approximately, 5-7 million people are infected with T. cruzi in the world, and approximately 10,000 people per year die of complications linked to this disease. METHODS: This work describes the construction of a new family of hidrazonoyl substituted derivatives, structurally designed exploring the molecular hybridization between megazol and nitrofurazone. RESULTS AND DISCUSSION: The compounds were evaluated for their in vitro activity against bloodstream trypomastigotes of Trypanosoma cruzi, etiological agent of Chagas disease, and for their potential toxicity to mammalian cells. CONCLUSION: Among these hydrazonoyl derivatives, we identified the derivative (4) that showed trypanocidal activity (IC50/24 h = 15.0 µM) similar to Bz, the standard drug, and low toxicity to mammalian cells, reaching an SI value of 18.7.
Asunto(s)
Hidrazonas/síntesis química , Hidrazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Técnicas de Química Sintética , Hidrazonas/química , Relación Estructura-Actividad , Tripanocidas/químicaRESUMEN
BACKGROUND: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes. OBJECTIVE: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. METHODS: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole. RESULTS: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 µM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 µM), which were almost equipotent to benznidazole (IC50=10.26 µM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice. CONCLUSION: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Células Cultivadas , Diseño de Fármacos , Macrófagos Peritoneales/efectos de los fármacos , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tripanocidas/químicaRESUMEN
[This corrects the article DOI: 10.1107/S2056989019012015.].
RESUMEN
The crystal structures of the disordered hemi-DMSO solvate of (E)-2-oxo-N'-(3,4,5-tri-meth-oxy-benzyl-idene)-2H-chromene-3-carbohydrazide, C20H18N2O6·0.5C2H6OS, and (E)-N'-benzyl-idene-2-oxo-2H-chromene-3-carbohydrazide, C17H12N2O3 (4: R = C6H5), are discussed. The non-hydrogen atoms in compound [4: R = (3,4,5-MeO)3C6H2)] exhibit a distinct curvature, while those in compound, (4: R = C6H5), are essential coplanar. In (4: R = C6H5), C-Hâ¯O and π-π intra-molecular inter-actions combine to form a three-dimensional array. A three-dimensional array is also found for the hemi-DMSO solvate of [4: R = (3,4,5-MeO)3C6H2], in which the mol-ecules of coumarin are linked by C-Hâ¯O and C-Hâ¯π inter-actions, and form tubes into which the DMSO mol-ecules are cocooned. Hirshfeld surface analyses of both compounds are reported, as are the lattice energy and inter-molecular inter-action energy calculations of compound (4: R = C6H5).
RESUMEN
The crystal structures of (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O-benzyl-oxime, C12H12N4O3, (I), (E)-1-methyl-5-nitro-1H-imidazole-2-carb-alde-hyde O-(4-fluoro-benz-yl) oxime, C12H11FN4O3, (II), and (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O-(4-bromo-benz-yl) oxime, C12H11BrN4O3, (III), are described. The dihedral angle between the ring systems in (I) is 49.66â (5)° and the linking Nm-C-C=N (m = methyl-ated) bond shows an anti conformation [torsion angle = 175.00â (15)°]. Compounds (II) and (III) are isostructural [dihedral angle between the aromatic rings = 8.31â (5)° in (II) and 5.34â (15)° in (III)] and differ from (I) in showing a near-syn conformation for the Nm-C-C=N linker [torsion angles for (II) and (III) = 17.64â (18) and 8.7â (5)°, respectively], which allows for the occurrence of a short intra-molecular C-Hâ¯N contact. In the crystal of (I), C-Hâ¯N hydrogen bonds link the mol-ecules into [010] chains, which are cross-linked by very weak C-Hâ¯O bonds into (100) sheets. Weak aromatic π-π stacking inter-actions occur between the sheets. The extended structures of (II) and (III) feature several C-Hâ¯N and C-Hâ¯O hydrogen bonds, which link the mol-ecules into three-dimensional networks, which are consolidated by aromatic π-π stacking inter-actions. Conformational energy calculations and Hirshfeld fingerprint analyses for (I), (II) and (III) are presented and discussed.
RESUMEN
In the non-planar title compound, C(16)H(14)N(2)O(2), the dihedral angle between the phenyl rings is 16.67â (8)°. An E conformation is found for each of the imine [1.286â (2)â Å] and ethyl-ene [1.335â (2)â Å] bonds. The amide O and H atoms are anti, and an intra-molecular hy-droxy O-Hâ¯N hydrogen bond is noted. The formation of N-Hâ¯O(hy-droxy) hydrogen bonds in the crystal packing leads to helical chains along the b axis. Supra-molecular layers in the ab plane are formed as the chains are linked by C-Hâ¯O inter-actions.
RESUMEN
In the title compound, C(16)H(14)N(2)O, the dihedral angle between the phenyl rings is 25.48â (12)°. An E conformation is found for each of the imine [1.269â (3)â Å] and ethyl-ene [1.313â (3)â Å] bonds. In the crystal, mol-ecules are linked by N-Hâ¯O hydrogen bonds, leading to zigzag chains along [010]. Supra-molecular layers in the ab plane are formed, whereby the chains are linked by C-Hâ¯N and C-Hâ¯π inter-actions.
RESUMEN
We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action.
Asunto(s)
Cinamatos/química , Diseño de Fármacos , Hidrazonas/síntesis química , Hidrazonas/farmacología , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Cisteína Endopeptidasas , Hidrazonas/química , Hidrazonas/toxicidad , Concentración 50 Inhibidora , Ratones , Proteínas Protozoarias/antagonistas & inhibidores , Tripanocidas/química , Tripanocidas/toxicidad , Trypanosoma cruzi/enzimologíaRESUMEN
The conformation about each of the imine and ethene bonds in the title hydrazide hydrate, C(16)H(13)ClN(2)O·H(2)O, is E. The hydrazide mol-ecule is approximately planar (r.m.s. deviation of the 20 non-H atoms = 0.172â Å). The most significant twist occurs about the ethene bond [C-C=C-C = 164.1â (5)°] and the dihedral angle formed between the benzene rings is 5.3â (2)°]. In the crystal, the presence of N-Hâ¯O(w) and O-Hâ¯O(c) (× 2; w = water and c = carbon-yl) hydrogen bonds leads to a supra-molecular array in the bc plane.
RESUMEN
The efficacy of two mesoionic derivatives (MI-H-H and MI-4-OCH(3)) was evaluated in CBA/J mice infected with Leishmania amazonensis. Treatment with these compounds demonstrated that the MI-4-OCH(3) derivative and the reference drug meglumine antimoniate (Glucantime) presented significant activity relative to an untreated control. No apparent hepatic or renal toxicity due to these mesoionic compounds was found.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmania mexicana , Leishmaniasis Cutánea/tratamiento farmacológico , Tiadiazoles/uso terapéutico , Animales , Antiprotozoarios/toxicidad , Recuento de Células Sanguíneas , Leishmaniasis Cutánea/sangre , Leishmaniasis Cutánea/psicología , Ganglios Linfáticos/parasitología , Meglumina/efectos adversos , Meglumina/uso terapéutico , Antimoniato de Meglumina , Ratones , Ratones Endogámicos CBA , Óxido Nítrico/metabolismo , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/uso terapéutico , Relación Estructura-Actividad , Tiadiazoles/toxicidadRESUMEN
In the title compound, C(16)H(14)N(2)O(2), the conformation about the C=C bond is E, and the two amide groups are effectively orthogonal [the C-N-N-C torsion angle is 104.5â (2)°]. In the crystal structure, the amide groups groups associate via N-Hâ¯O hydrogen bonding, forming supra-molecular tapes with undulating topology along the c-axis direction.
RESUMEN
In the title mol-ecule, C(9)H(8)N(4)O(2)S, the dihedral angle between the thia-diazole and benzene rings is 73.92â (8)° and the thia-diazole group S atom is orientated towards the benzene ring, the central S-C-C-C torsion angle being 45.44â (18)°. In the crystal, supra-molecular tapes mediated by N-Hâ¯N hydrogen bonds and comprising alternating eight-membered {â¯HNCN}(2) and 10-membered {â¯HNHâ¯NN}(2) synthons are formed along [010]. The tapes are consolidated into a three-dimensional network by a combination of C-Hâ¯O, C-Hâ¯S and C-Hâ¯π inter-actions.
RESUMEN
In the title compound, C(16)H(13)N(3)O(4), the dihedral angle between the terminal benzene rings is 14.02â (7)°. The carbonyl groups are anti with respect to each other, which facilitates their participation in the formation of supra-molecular chains. Each side of the -C(=O)N(H)N(H)C(=O)- residue associates with a centrosymmetrically related mol-ecule, resulting in the formation of essentially flat ten-membered {â¯O=CNN(H)}(2) synthons. The resultant chains are further consolidated in the crystal structure via C-Hâ¯O contacts.
RESUMEN
L-arginine is involved in the production of both nitric oxide (NO), mediated by nitric oxide synthase (NOS) and L-ornithine, by arginase activity. It is generally accepted that NO regulation occurs mainly at the transcriptional level of NOS. In a previous work we purported that there is evidence that Leishmania sp. can produce NO from L-arginine. An arginase activity in its gene sequence has also been reported in Leishmania parasites. In a search for intracellular targets as potential antileishmanicidal agents, such as the L-arginine metabolism, we used 1,3,4-thiadiazolium mesoionic compounds, that have been demonstrated to be cytotoxic to the Leishmania amazonensis, when compared to Pentamidine isethionate as a reference drug. Parasites were assayed in absence/presence of 4'- and 3'-methoxy mesoionic derivatives in order to verify the effect on NO production and arginase activity in L. amazonensis. The results indicated that the drugs reduce from 70 to 90% of the NO production by the parasite and act on a soluble nitric oxide synthase purified from L. amazonensis promastigotes and axenic amastigotes.
Asunto(s)
Arginasa/efectos de los fármacos , Leishmania mexicana/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Tiadiazoles/química , Tiadiazoles/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Leishmania mexicana/enzimología , Óxido Nítrico/antagonistas & inhibidores , Nitritos/análisis , Sales (Química) , Relación Estructura-ActividadRESUMEN
Megazol is a highly active compound against Trypanosoma cruzi, and has become a core structure for the design of new trypanocidal agents. Recently, we have identified the new potent trypanocide agent Brazilizone A, which presents an IC(50) twofold more potent than the prototype megazol. This result has encouraged us to further explore structurally-related 1,3,4-thiadiazole-2-arylhydrazone derivatives, in order to get a better understanding of their structural and antiprotozoal activity relationships. Herein we report the synthesis and trypanocidal profile of thirteen new Brazilizone A analogues, which supported the construction of 3D-QSAR models used for its structural optimization.
Asunto(s)
Hidrazonas/síntesis química , Hidrazonas/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Tripanocidas/síntesis química , Animales , Cristalografía por Rayos X , Hidrazonas/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad , Tiadiazoles/química , Tripanocidas/farmacología , Trypanosoma/efectos de los fármacosRESUMEN
In this work, we report the synthesis and the antimycobacterial evaluation of new trans-cinnamic acid derivatives of isonicotinic acid series (5) and benzoic acid series (6), designed by exploring the molecular hybridization approach between isoniazid (1) and trans-cinnamic acid derivative (3). The minimum inhibitory concentration (MIC) of the compounds 5a-d and 6c exhibited activity between 3.12 and 12.5 microg/mL and could be a good start point to find new lead compounds against multi-drug resistant tuberculosis.
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Cinamatos/química , Hidrazinas/química , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrolloRESUMEN
In this first study, a series of mesoionic compounds like 1,3,4-thiadiazolium-2-phenylamine derivatives were synthesized and studied in Leishmania amazonensis. The cytotoxic effects of these compounds on the host cells were investigated and the antileishmanial in vitro activity was compared with other species of Leishmania (Leishmania chagasi and Leishmania braziliensis). The compounds presented lower toxicity in murine macrophages than the reference drug pentamidine. The halogen derivatives 5, 6, 8 and 13 (4-F, 4-Cl, 4-Br and 3-Cl) were the most active compounds among all the species tested.
Asunto(s)
Antiprotozoarios/farmacología , Antiprotozoarios/toxicidad , Leishmania/química , Leishmania/efectos de los fármacos , Animales , Antiprotozoarios/efectos adversos , Concentración de Iones de Hidrógeno , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
In this work we reported the synthesis and the trypanocidal profile of new 1,3,4-thiadiazole-2-arylhydrazone derivatives of nitroimidazole series (4) or phenyl series (5), designed by exploring the molecular hybridization approach between megazol (2) and guanyl hydrazone derivative (3). The evaluation of the activity against bloodstream trypomastigote forms of Trypanosoma cruzi forms lead us to identify a new potent trypamomicide prototype, that is, brazilizone A (4k), which present an IC50/24 h=5.3 microM.