Semicarbazonas e tiossemicarbazonas: o amplo perfil farmacológico e usos clínicos

This article shows that thiosemicarbazones, semicarbazones and their metal complexes can exhibit target selectivity along with a wide pharmacological profile. Complexes of thiosemicarbazones with cytotoxic or antitumoral activity are presented, some of which show activity against cisplatinum-resistant cells. The inhibition mechanism of the enzyme ribonucleoside diphosphate reductase (RDR), involved in DNA syntheses, by alpha(N)-heterocyclic thiosemicarbazones is discussed. The encouraging results of clinical trials with the RDR inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone ("Triapine") against rapidly growing tumors are outlined. Examples are also given of thiosemicarbazones with antiviral and antimicrobial activity. The possible applications of semicarbazones as anticonvulsants with low toxicity and good therapeutic index are presented.

Tiossemicarbazonas: métodos de obtenção, aplicações sintéticas e importância biológica

Thiosemicarbazones are a class of compounds known by their chemical and biological properties, such as antitumor, antibacterial, antiviral and antiprotozoal activity. Their ability to form chelates with metals has great importance in their biological activities. Their synthesis is very simple, versatile and clean, usually giving high yields. They are largely employed as intermediates, in the synthesis of others compounds. This article is a survey of some of these characteristics showing their great importance to organic and medicinal chemistry.

Síntese e avaliação da atividade antimicrobiana de novas 4-tiazolidinonas obtidas a partir de formilpiridina tiossemicarbazonas

Twelve novel 4-thiazolidinone derivatives (2a-l) have been synthesized by reacting formilpyridine thiosemicarbazones (1a-l) and anhydride maleic in toluene. Their chemical structures were confirmed by IR, ¹H and 13C NMR. The new compounds were submitted to in vitro evaluation against pathogenic Gram-positive, Gram-negative bacteria and yeasts. The findings obtained showed that the compounds 2a, 2d, 2e and 2g were effective against some of the bacterial strains used, whereas the compounds 2d, 2e and 2i exhibited a moderate antifungal activity against the yeast strains evaluated. An initial structure activity relationship (SAR) was established.

Avaliação do potencial anticorrosivo de tiossemicarbazonas solubilizadas em microemulsão

In this paper, thiosemicarbazones 4-N-cinnamoyl-thiosemicarbazone (CTSC), 4-N-(2'-methoxycinnamoyl)-thiosemicarbazone (MCTSC), and 4-N-(4'-hydroxy-3'-methoxybenzoyl)- thiosemicarbazone (HMBTSC) were solubilized in an oil-in-water (O/W) microemulsion system (ME_OCS), forming systems CTSC_ME_OCS, MCTSC_ME_OCS and HMBTSC_ME_OCS. The effectiveness of these systems in the process of inhibiting AISI 1020 carbon steel corrosion was evaluated in a saline solution (NaCl 0.5%), using a galvanostatic method. The tested thiosemicarbazones showed higher inhibitory effects (85.7% for CTSC_ME_OCS, 84.0% for MCTSC_ME_OCS, and 83.3% for HMBTSC_ME_OCS). The surfactant OCS (dissolved in H2O) and the ME_OCS system showed lower efficacies, with 71.0% for OCS and 74.0% for ME_OCS system.

Avaliação do potencial anticorrosivo de tiossemicarbazonas solubilizadas em sistemas microemulsionados

In this work thiosemicarbazones [4-N-cinnamoyl-thiosemicarbazone (CTSC), 4-N-(2'-methoxycinnamoyl)-thiosemicarbazone (MCTSC), and 4-N-(4'-hydroxy-3'-methoxybenzoyl)-thiosemicarbazone (HMBTSC)] were solubilized in an microemulsion system (ME_OCS) which is rich in aqueous phase (O/W system). The system ME_OCS was obtained with saponified coconut oil (OCS) as (surfactant), butanol (cosurfactant), and kerosene as oil phase (Fo), using 40% of C/T (cosurfactant/surfactant), 5% of Fo and 55% of aqueous phase. The microemulsions systems CTSC_ME_OCS, MCTSC_ME_OCS and HMBTSC_ME_OCS effectiveness on a AISI 1020 carbon steel corrosion inhibition process were evaluated in a saline solution (NaCl 0.5%), using a galavostatic method. The tested thiosemicarbazones (TSC) showed highest inhibitors effects (85.7% for CTSC_ME_OCS, 84.0% for MCTSC_ME_OCS, and 83.3% HMBTSC_ME_OCS) at lower concentrations [0.19% of CTSC, 0.07% (MCTSC), and 0.26% (HMBTSC)]. Comparatively, the surfactant OCS (solubilized in H2O) as well as the system ME_OCS showed lower efficacy [71% for OCS (at 0.20 - 0.25% of concentration) and 74% for ME_OCS (at 0.5% of concentration)]. Since the microemulsion systems ME_OCS showed satisfactory interfacial adsorption, the greatest inhibitory effect of those TSC_ME_OCS systems could be correlated to both chemical composition of each tested TSC (which is rich in heteroatoms and aromatic ring) and also the presence of the surfactant OCS

Síntese e caracterização de ligantes oximas e tiossemicarbazonas e seus complexos

Este trabalho apresenta a síntese e caracterização de cinco ligantes e quatro complexos derivados de oximas e tiossemicarbazonas. Entre essas, discutem-se as estruturas cristalinas/moleculares determinadas por difração de raios-X em monocristais: do ligante 4-feniltiossemicarbazida-isatina (Ligante 5), do complexo piridina-salicilaldeído-4- feniltiossemicarbazona de niquel (II) (Complexo 1), e do bis-4-feniltiossemicarbazonaisatina de chumbo(II) (Complexo 2). A estrutura do Ligante 5 cristaliza no sistema monoclínico, grupo espacial P21/c, com parâmetros de cela a = 6,3227(2) Å, b = 15,7973(7) Å, c = 14,4572(6) Å, β = 93,9330(10)°, V = 1440,61(10) Å3 , Z = 4. O refinamento da estrutura convergiu aos índices de discordância finais R1 = 0,0520, wR2 = 0,1471. Observa-se ainda a ocorrência de interações intermoleculares do tipo ligações de hidrogênio clássicas [N18−H3---O1′ 2,907(2)Å], com a formação de estruturas dímeras inter-relacionadas por simetria dentro da cela cristalina. Para a estrutura cristalina do Complexo 1, observa-se NC=4, e geometria de coordenação quadrada plana, onde o ligante saliciladeído-4-feniltiossemicarbazida comporta-se como quelante tridentado, e completando a esfera de coordenação do centro metálico temos uma molécula de piridina. A estrutura cristaliza no sistema monoclínico, grupo espacial P21/m, parâmetros de cela a = 12,8211(2) Å, b = 5,73370(10) Å, c = 23,9950(4) Å, β = 101,0910(10)°, V = 1730,98(5) Å3 , índices de discordância finais R1= 0,0320, wR2 = 0,0888, Z=3. O Complexo 1 apresenta ainda interações intermoleculares do tipo [N(3)-H(3)---S(1) = 3,5838(17)º, N(3)–H(3A)---S(1) = 160,91(19)º], formando estruturas dímeras e ligação de hidrogênio intramolecular não-clássica do tipo [C(10)-H(10)---N(2) = 2,838(2)º e C(10) – H(10)---N(2) = 122º]. A estrutura cristalina do complexo 2, apresenta duas formas independentes (uma com centro representado por Pb1 e outra por Pb2). Para a unidade com Pb1 temos o complexo composto por duas unidades do Ligante 5, que comportam-se como quelantes tridentados, e a esfera de coordenação é completada por interações intermoleculares do tipo η 2 areno π e através da ligação polarizada com o O1 da moléculas vizinha, o que confere ao íon Pb1 NC=9. A unidade Pb2 apresenta apenas as duas unidades do Ligante 5 coordenadas conferindo-lhe NC=6. A estrutura cristaliza no sistema monoclínico, grupo espacial C2/c, parâmetros de cela a = 37,9747(6) Å, b= 9,51280(10) Å, c = 31,4378(5) Å, β = 125,951(2)°, V= 9193,5(2) Å3 , Z = 4, índices de discordância finais= R1 = 0,0643, wR2 = 0,1227.

Atividade anti - Mycobacterium tuberculosis intra e extracelular e citoxicidade dos complexos de rutênio e vanádio e seus ligantes

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Inovação do método MIA-QSAR: aplicação para doenças tropicais negligenciadas

Multivariate image analysis applied to the quantitative structure-activity relationships (MIA-QSAR) is a 2D QSAR technique that has been presenting promising outcomes for the development of new drug candidates, due to its simplicity, rapidity and low cost. In this way, the present study aims at introducing, consolidating and improving the new dimensions named aug-MIA-QSAR and aug-MIA-QSARcolor, as well as applying them to the study of neglected diseases, in order to obtain new drug targets using chemico-biological interpretation of the MIA molecular descriptors. Four compound data sets with experimental bioactivities against Chagas disease, malaria, dengue and schistosomiasis were evaluated using three approaches: MIA-QSARt, aug-MIA-QSAR and aug-MIA-QSARcolor. In general, representations of atoms as spheres with different colors and sizes proportional to the corresponding van der Waals radii (aug-MIA approaches) improved the predictive ability and interpretability in all data sets. The use of colors proportional to the Pauling´s electronegativity showed that MIA descriptors are capable of identifying periodic properties relevant for the studied activity. Finally, solid colors instead of spotlighted atoms allowed a correct identification of atoms by means of pixel values in the studies for malaria, dengue and schistosomiasis, which were, subsequently, useful for the chemical interpretation related to the bioactivity. It can be inferred that semicarbazones and thiosemicarbazones derivative with a tri-substituted ring in R1 group and a trifluoro methyl group in the R 3 position instead of a chlorine antitripanossoma resulted in higher activity. The antimalarial activity of quinolon-4(1H)imines can be improved if: 1) R1 and R2 are electron donor groups, 2) R3 has long aminoalkyl chains, and 3) R4 possesses substituents with big atomic volume. In the study for dengue, it was found that tetrapeptides with unbranched small size amino acids in the A1 and A4 positions can increase the substrate affinity (Km) to the NS3 protein, and when in A1 and A2 positions, the substrate cleavage rate (kcat). On the other hand, acidic amino acids in the A2 and A4 positions were found to be related with low substrate affinity to the NS3 protein and when present in A1, with low substrate cleavage rate. Finally, the presence of metoxy substituents in R1 (or R2) and R5 in the neolignan backbone can favor their antischistosomal activity.

Cobalt(III) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Síntese e caracterização de ligantes nitrogenados derivados de isatina, 4-benziltiossemicarbazida e seus complexos com metais d¹º

Neste trabalho são apresentadas e discutidas as estruturas cristalinas e moleculares do ligante (1), isatina-3-(toluilsulfono-hidrazona), dos complexos [bis(2-acetilpiridina-N4 - benziltiossemicarbazona-N,N,S)Cd(II)], (1), [bis (isatina-3-N4 -benziltiossemicarbazonaN,S)Hg(II)].Etanol, (2) e [bis (isatina-3-N4 -benziltiossemicarbazona-N,S,O)Zn(II)].DMF, (3). Cristais amarelos vítreos do ligante (1) foram obtidos a partir da evaporação lenta de etanol do ensaio de cristalização. Seus dados cristalográficos indicam que duas moléculas interagem através de ligações de hidrogênio do tipo N1-H···O1, formando unidades dímeras. A reação entre 2-acetilpiridina-N4 -benziltiossemicarbazona e Cd(CH3COO)2.2H2O, em presença de etanol, KOH, e após evaporação lenta da mistura de acetona e DMF(2:1), resultou em cristais amarelos do complexo (1). As interações do tipo C(10)-H(10)···S(1)···H(1)-N(4), e N(8)- H(29)⋅⋅⋅S(2) permitem a dimerização do complexo, e a formação de uma cadeia unidimensional. Os cristais laranja do complexo (2) foram obtidos da reação entre o ligante isatina-3-N4 -benziltiossemicarbazona e Hg(NO3)2.H2O, na presença de metanol, KOH, e após evaporação lenta de uma mistura de tolueno e acetona (2:1). As moléculas do complexo (2) estão associadas por ligações de hidrogênio do tipo N(63)-H(4)···O(21), essas interações centrossimétricas conduzem a formação de dímeros. A reação entre o ligante isatina-3-N4 - benziltiossemicarbazona e Zn(CH3COO)2.2H2O, em presença de etanol e KOH resultou em cristais de coloração laranja do complexo (3). A estrutura do complexo apresenta múltiplas ligações de hidrogênio, com formação de dímeros através das interações N1-H1···O1 e C3- H3···N(7). Os dímeros associam-se por interações N4-H4···O2 numa cadeia unidimensional ao longo da direção cristalográfica [100]. A polimerização bidimensional é observada 7 considerando-se as interações do tipo C20-H20···S1, N8-H8···S2 ao longo da direção cristalográfica [010], bem como das interações, N5-H5···O3DMF e C31-H31B···Car, que ocorrem através da molécula de solvente DMF.