Crystallographic study of organic compounds with potential herbicide activity

Isobenzofuran-1(3H)-onas (phthalides) derivatives are an important class of compounds displaying a variety of biological effects, such as antibacterial, antioxidant, anticonvulsant, anti-HIV. Order to obtain new herbicides, five phthalides derivatives were synthesized and demonstrated the ability to inhibit the radicle growth of different species. In this work are presented the results of structural elucidation by X-ray diffraction, of five new compounds:  Compound 1: C9H8O3 6-Methoxyisobenzofuran-1(3H)-one;  Compound 2: C9H8O3 5-Methoxyisobenzofuran-1(3H)-one;  Compound 3: C8H6O3 6- hydroxy isobenzofuran-1(3H)-one;  Compound 4: C8H6O3 5- hydroxy isobenzofuran-1(3H)-one;  Compound 5: C16H16O4 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1- enyl)isobenzofuran-1(3H)-one. Four compounds crystallize in the monoclinic system (three in centrosymmetric space groups and one in non-centrosymmetric space group) and one crystallizes in the triclinic system. In compounds 1-4 the molecule is essentially planar with root mean-square (r.m.s) deviation to the fitted non-hydrogen atoms ranging from 0.010 Å to 0.016 Å. In compound 5, which crystallizes with two molecules per asymmetric unit, the phthalide portion is essentially planar with r.m.s. deviation for fitted atoms of 0.027 Å and 0.024 Å for molecules a and b, respectively. In the crystal packing of methoxylated compounds are present weak intermolecular interactions of the type C H···X (X =  and O). In the other hand, in the hydroxylated compounds there are strong hydrogen bonds O H···O. The compound 3 also shows weak interactions of the type C H···O. In the crystal packing of compound 5, Resonance Assisted Hydrogen Bond (RAHB) links the molecules b in an infinite polymeric network along the direction [101]. There are also C H···O and O H···O intermolecular interactions between molecules a and b of the asymmetric unit. All compounds show weak aromatic   stacking interactions.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorMestre em QuímicaDerivados de isobenzofuran-1(3H)-onas (ftalidas) representam uma importante classe de compostos devido ao seu amplo espectro de atividades biológicas como, por exemplo, antibacteriana, antioxidante, anticonvulsivante, anti-HIV. Visando obter novos herbicidas, cinco derivados de ftalidas foram sintetizados e evidenciaram capacidade em inibir o crescimento radicular de diferentes espécies. Neste trabalho são apresentados os resultados da elucidação estrutural, por difração de raios X, dos cinco compostos:  Composto 1: C9H8O3 6-Metoxiisobenzofuran-1(3H)-ona;  Composto 2: C9H8O3 5-Metoxiisobenzofuran-1(3H)-ona;  Composto 3: C8H6O3 6-Hidroxiisobenzofuran-1(3H)-ona;  Composto 4: C8H6O3 5-Hidroxiisobenzofuran-1(3H)-ona;  Composto 5: C16H16O4 3-(2-hidróxi-4,4-dimetil-6-oxocicloex-1- enil)isobenzofuran-1(3H)-ona. Quatro compostos cristalizam no sistema monoclínico (três compostos em grupos espaciais centrossimétricos e um composto em grupo não centrossimétrico) e um no sistema triclínico. Nos compostos de 1 a 4 a molécula é essencialmente planar com raiz quadrada do desvio quadrático médio do plano traçado por todos os átomos não hidrogenóides, variando de 0,010 Å a 0,016 Å. No composto 5, que cristaliza com duas moléculas por unidade assimétrica, a porção referente a ftalida é essencialmente planar com raiz quadrada do desvio quadrático médio do plano traçado por todos os átomos não hidrogenóides de 0,027 Å e 0,024 Å, para as moléculas a e b, respectivamente. No empacotamento cristalino dos compostos metoxilados estão presentes interações intermoleculares fracas do tipo C H···X (X =  e O). Já nos compostos hidroxilados estão presentes ligações de hidrogênio forte do tipo O H···O. O composto 3 também apresenta interações fracas do tipo C H···O. No empacotamento cristalino do composto 5, ligações de hidrogênio assistidas por ressonância (RAHB) ligam as moléculas b numa rede polimérica ao longo da direção [101]. Interações do tipo C H···O e O H···O ocorrem entre as moléculas a e b da unidade assimétrica. Interações do tipo   stacking estão presentes nos cinco compostos estudados

Synthesis, characterization and biological studies of copper(II) complexes containing hydrazides and N,N-donors ligands

This work describes the synthesis of twenty novel ternary copper(II) complexes with hydrazides (4-fluorophenoxyacetic acid hydrazide (4-FH), 4-nitrobenzoic hydrazide (4-NH), benzhydrazide (BH), 2-chlorobenzhydrazide (2-CH), 4-chlorobenzhydrazide (4CH), 2-methoxybenzhydrazide (2-MH) or 4-methoxybenzhydrazide (4-MH)) and N,Ndonor ligands (1,10-phenanthroline (phen), 2,2-bipyridine (bipy) or 4-4′-dimethoxy-2-2′bipyridine (dmb)). These complexes were characterized by elemental analysis (CHN), conductivity measurements, FT-IR, UV-Vis and high-resolution electrospray ionization mass spectrometry (HRESIMS). The structures of two coordination compounds were elucidated by single crystal X-ray analysis. In all the complexes, the copper is bound in a bidentate manner to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. The labilization of the axial ligands in solution (perchlorate anions) result in the generation of compounds of type [Cu(N–O)(N– N)]2+. Regarding the clinical utility of these complexes, the cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and [Cu(phen)2]2+. Considering the cytotoxicity results, further investigations for the compounds Cu(4FH)(phen)(ClO4)2 and Cu(4-NH)(phen)(ClO4)2∙H2O were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38 × 104 and 2.62 × 104, respectively. Thereafter, thirteen copper complexes were evaluated for their trypanocidal and cytotoxic activities. Several complexes were more active than free ligands and benznidazole, a drug used in the treatment of Chagas disease. The selectivity index calculated for two copper complexes was higher than recommended for subsequent tests. These findings are very important and make these compounds candidates for preclinical studies in vitro and in vivo.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas GeraisFAU - Fundação de Apoio UniversitárioIQUFU - Instituto de Química da Universidade Federal de UberlândiaRQMG - Rede Mineira de QuímicaTese (Doutorado)O câncer e a doença de chagas são enfermidades que acometem a população. Os efeitos colaterais indesejáveis causados pelo uso dos quimioterápicos, associados à capacidade das células tumorais de desenvolverem resistência intrínseca ou adquirida aos medicamentos disponíveis no mercado, impulsionam a busca por novos fármacos que sejam mais ativos e seletivos e, consequentemente menos agressivos ao organismo. No que se refere ao tratamento da doença de chagas, apenas os fármacos nifurtimox e benzonidazol estão disponíveis no mercado. Com a baixa quantidade e efetividade desses fármacos, fica evidente que a busca por novos agentes anti-Trypanosoma cruzi é necessária para aumentar o arsenal de drogas atualmente disponíveis para tratar essa doença. Assim, diversas pesquisas estão sendo realizadas com o intuito de obter novos agentes antitumorais e tripanocidas que possuam um potencial farmacológico mais satisfatório do que os medicamentos disponíveis na clínica médica. O presente trabalho descreve a síntese de vinte novos complexos ternários de cobre(II) com hidrazidas (4-fluoro-fenoxiacético-hidrazida (4-FH), 4-nitro-benzil-hidrazida (4-NH), benzil-hidrazida (BH), 2-cloro-benzil-hidrazida (2-CH), 4-cloro-benzil-hidrazida (4-CH), 2-metóxi-benzil-hidrazida (2-MH) ou 4-metóxi-benzil-hidrazida (4-MH)) e ligantes N,N-doadores (1,10-fenantrolina (phen), 2,2 -bipiridina (bipy) ou 4-4'-dimetoxi-2-2'-bipiridina (dmb)). Os complexos foram caracterizados por análise elementar, medidas de condutividade, espectrometria de massa com ionização por eletrospray (ESI-MS) e por espectroscopia de UV-Vis e IV. As estruturas cristalinas dos complexo 1 e 9 foram determinadas por difração de raios X por monocristais. Em todos os complexos, o íon cobre(II) é coordenado de modo bidentado pela hidrazida através dos átomos de nitrogênio terminal e do oxigênio da carbonila, e às bases heterocíclicas através dos seus dois átomos de nitrogênio. A labilização dos ligantes axiais em solução (ânion perclorato) resulta na produção de compostos do tipo [Cu(N–O)(N–N)]2+. A atividade citotóxica dos compostos foi investigada em três linhagens tumorais (K562, MDA-MB-231 e MCF-7). No que diz respeito à linhagem celular K562, os complexos de cobre(II) com 1,10-fenantrolina exibem expressiva atividade citotóxica e são mais ativos do que carboplatina, os ligantes livres e [Cu(phen)2]2+. Considerando estes resultados, estudos adicionais foram realizados para os compostos Cu(4-FH)(phen)(ClO4)2 e Cu(4-NH)(phen)(ClO4)2∙H2O. A análise de citometria de fluxo revelou que esses complexos induzem a morte celular por apoptose na linhagem celular MDA-MB-231 e se ligam ao DNA com valores de K de 4,38 × 104 e 2,62 × 104, respectivamente. Posteriormente, foram avaliados treze complexos de cobre quanto às suas atividades tripanocidas e citotóxicas. Vários complexos foram mais ativos que os ligantes livres e o benzonidazol, um fármaco utilizado no tratamento da doença de Chagas. O índice de seletividade calculado para os complexos 9 e 20 foi maior que o recomendado para testes subseqüentes, sugerindo que estes compostos são bons candidatos para estudos pré-clínicos in vitro e in vivo

A Ternary Copper (II) Complex with 4-Fluorophenoxyacetic Acid Hydrazide in Combination with Antibiotics Exhibits Positive Synergistic Effect against Salmonella Typhimurium

Salmonella spp. continues to figure prominently in world epidemiological registries as one of the leading causes of bacterial foodborne disease. We characterised 43 Brazilian lineages of Salmonella Typhimurium (ST) strains, characterized drug resistance patterns, tested copper (II) complex as control options, and proposed effective antimicrobial measures. The minimum inhibitory concentration was evaluated for seven antimicrobials, isolated and combined with the copper (II) complex [Cu(4-FH)(phen)(ClO4)2] (4-FH = 4-fluorophenoxyacetic acid hydrazide and phen = 1,10-phenanthroline), known as DRI-12, in planktonic and sessile ST. In parallel, 42 resistance genes were screened (PCR/microarray). All strains were multidrug resistant (MDR). Resistance to carbapenems and polymyxins (86 and 88%, respectively) have drawn attention to the emergence of the problem in Brazil, and resistance is observed also to CIP and CFT (42 and 67%, respectively), the drugs of choice in treatment. Resistance to beta-lactams was associated with the genes blaTEM/blaCTX-M in 39% of the strains. Lower concentrations of DRI-12 (62.7 mg/L, or 100 μM) controlled planktonic and sessile ST in relation to AMP/SUL/TET and AMP/SUL/TET/COL, respectively. The synergistic effect provided by DRI-12 was significant for COL/CFT and COL/AMP in planktonic and sessile ST, respectively, and represents promising alternatives for the control of MDR ST

Copper(II) Complex Containing 4-Fluorophenoxyacetic Acid Hydrazide and 1,10-Phenanthroline: A Prostate Cancer Cell-Selective and Low-Toxic Copper(II) Compound

Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men worldwide. The treatment of advanced cases is based on chemotherapy, which lacks specificity and efficacy, due to severe side effects and resistance to the traditional drugs. Copper complexes have shown antitumoral efficacy and low toxicity, being considered a promising class of metal-based drugs for the treatment of malignant neoplasms. Thus, the present study aimed to evaluate the cellular effects of a copper(II) complex with 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline (1) on PCa cell lines, as well as the mutagenic/recombinogenic and anticarcinogenic potential of 1 in Drosophila melanogaster. PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (androgen-independent PCa) cells were cultured, and cytotoxicity was assessed using the MTT assay. The expression levels of the proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry. Furthermore, the Somatic Mutation and Recombination Test (SMART) and the Epithelial Tumor Test (ETT) were performed. Complex 1 was selective to LNCaP cells, significantly reducing Ki-67 and Cyclin D1 expression levels. Sub-toxic concentrations of complex 1 were defined by the toxicity test in D. melanogaster, and no mutagenic/recombinogenic/carcinogenic effects were observed. Anticarcinogenic potential was observed in D. melanogaster, suggesting modulating activity of the complex 1 against Doxorubicin, a drug used as control by its carcinogenic properties. Therefore, complex 1 is a possible starting point for the development of new antitumor agents for the treatment of PCa