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1.
Int J Mol Sci ; 22(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638665

RESUMO

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2-5.6-fold) and suppressed cyclin D expression (0.8-0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.


Assuntos
Ácidos Hidroxâmicos/farmacologia , Bases de Mannich/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Triazóis/farmacologia , Antineoplásicos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Micro-Ondas , Simulação de Acoplamento Molecular , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 223: 113646, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34182359

RESUMO

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.


Assuntos
Benzimidazóis/química , Desenho de Fármacos , Imidazóis/química , Bases de Mannich/química , Tripanossomicidas/síntese química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Bases de Mannich/farmacologia , Bases de Mannich/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/fisiologia
3.
Eur J Med Chem ; 220: 113459, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33915373

RESUMO

The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 µM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7-5.1 µM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Bases de Mannich/farmacologia , Fenóis/farmacologia , Animais , Antibacterianos/química , Antioxidantes/química , Artemia , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Bases de Mannich/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenóis/química , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade
4.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916955

RESUMO

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a-l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a-d, respectively. The in vitro inhibitory activity of compounds 4a-l and 5a-d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5-8 µg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bases de Mannich/química , Bases de Mannich/farmacologia , Oxidiazóis/química , Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Bases de Mannich/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
5.
J Med Chem ; 64(8): 5198-5215, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844521

RESUMO

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.


Assuntos
Antimaláricos/química , Benzimidazóis/química , Hemeproteínas/metabolismo , Bases de Mannich/química , Microtúbulos/metabolismo , Administração Oral , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Resistência a Medicamentos/efeitos dos fármacos , Estabilidade de Medicamentos , Meia-Vida , Hemeproteínas/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Microtúbulos/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/fisiologia , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 35: 116074, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640707

RESUMO

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 µM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 µM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, disaggregation ability on Aß1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Compostos de Benzilideno/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cobre/farmacologia , Relação Dose-Resposta a Droga , Electrophorus , Feminino , Humanos , Masculino , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
7.
Bioorg Chem ; 107: 104629, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33482607

RESUMO

The design, synthesis and identification of a novel series of Mannich bases of ciprofloxacin was reported. Naphthol derivatives 2a and 2b showed highly potent cytotoxic activity among the tested compounds. Compound 2a showed broad spectrum antiproliferative activity with GI50 of 2.5-6.79 µM with remarkable selectivity towards renal and prostate cancers with selectivity ratios ranging from 0.17 to 6.79. Independently, 2a showed outstanding activity against colon cancer HOP-92 cell lines with IC50 of 6.66 µM while 2b showed highly potent activity against ovarian cancer cell lines with IC50 of 0.97 µM. Results showed that 2b induced cell cycle arrest at G2/M phase and apoptosis; compound 2b showed over-expression of caspase-3 protein level (449.2 ± 7.95) compared to doxorubicin (578.7 ± 14.4 pg/mL). Meanwhile, compounds 2a and 2b experienced outstanding activity against both Gram-positive and Gram-negative microorganisms. Interestingly, compound 2j experienced high activity against Escherichia coli and Pseudomonas aeruginosa with MIC of 0.036 and 0.043, respectively. Compound 2d revealed 27 folds and 22 folds, respectively increasing of activity over ciprofloxacin against Staphylococcus aureus and MRSA(reference strain). Compound 2d showed high activity against Staphylococcus aureus, MRSA (reference strain) and MRSA (clinical strain) with MIC of 0.57, 0.52, 0.082 µg/mL, respectively. Interestingly, the most active tested compounds were found to have promising physicochemical and drug likeness properties. The Mannich bases 2j, 2d and 2g showed promising antibacterial activities, while naphthols 2a and 2b showed promising antiproliferative and antibacterial activities that require further optimization.


Assuntos
Antibacterianos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Ciprofloxacina/química , Bases de Mannich/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Caspase 3/química , Domínio Catalítico , Linhagem Celular Tumoral , Ciprofloxacina/metabolismo , Ciprofloxacina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Solubilidade
8.
Int J Biol Macromol ; 172: 299-308, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33418048

RESUMO

As one of the most significant natural polymer with the highest annual yield, lignin has been applied in the treatment of wastewater to remove heavy metal ions. However, there are still some shortages, such as low reactivity, difficulties in adsorbing oxyanions and low selectivity on specific oxyanions. To improve its adsorption properties, a novel lignin-based adsorbent was prepared in this study, doped with nitrogen by Mannich reaction, using triethylenetetramine (TETA) as N source, and further modified with Ca2+. The adsorption of Ca, N-co-doped lignin (Ca@N-Lig) for As (V), Cr (VI) and P (V) was studied. The Ca@N-Lig shows high capacity, excellent selectivity and prominent regeneration ability for As (V) adsorption. The adsorption of Ca@N-Lig for As (V) followed the Langmuir isotherm model and the pseudo-second-order kinetics model, yielding a maximum adsorption capacity of 681.59 mg·g-1 and a fast adsorption equilibrium within 30 min. Ca@N-Lig has an excellent regeneration ability on the adsorption of As (V) with a decrease of about 15.60% after 5 adsorption/desorption cycles. This study offers an efficient way to remove As (V) from polluted water.


Assuntos
Arsênio/isolamento & purificação , Cálcio/química , Lignina/química , Nitrogênio/química , Trientina/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Reutilização de Equipamento , Água Doce/química , Humanos , Cinética , Bases de Mannich/química , Águas Residuárias/química , Purificação da Água/métodos
9.
Bioorg Chem ; 107: 104524, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33317836

RESUMO

The synthesized Schiff Bases were reacted with formaldehyde and secondary amine such as 2,6-dimethylmorpholine to afford N-Mannich bases through the Mannich reaction. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were treated with 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize eight new 1-(2,6-dimethylmorpholino-4-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4a-h). The structures of the synthesized eight new compounds were characterized using IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Synthesized compounds inhibitory activity determined against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes with Ki values in the range 25.23-42.19 µM for AChE, 19.37-34.22 µM for BChE, and 21.84-41.14 µM for GST, respectively. Binding scores of most active inhibitors against AChE, BChE, and GST enzymes were detected as -10.294 kcal/mol, -9.562 kcal/mol, and -7.112 kcal/mol, respectively. The hydroxybenzylidene moiety of the most active inhibitors caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond.


Assuntos
Inibidores da Colinesterase/farmacologia , Bases de Mannich/farmacologia , Morfolinas/farmacologia , Bases de Schiff/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CACO-2 , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Cães , Desenho de Fármacos , Ensaios Enzimáticos , Glutationa Transferase/antagonistas & inibidores , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Células Madin Darby de Rim Canino , Bases de Mannich/síntese química , Bases de Mannich/metabolismo , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/metabolismo , Ligação Proteica , Bases de Schiff/síntese química , Bases de Schiff/metabolismo
10.
Turkiye Parazitol Derg ; 44(4): 216-220, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33269563

RESUMO

Objective: Leishmaniasis is an important parasitic disease in many countries, including ours. A variety of drugs are currently used for its treatment. However, certain side effects of these drugs, such as teratogenicity, hepatotoxicity and nephrotoxicity, have been reported in some patients. The goal of this research is to determine the antileishmanial effects of eight different previously synthesised compounds containing Schiff and Mannich bases (morpholine) against Leishmania infantum (L. infantum) promastigotes by the liquid microdilution method utilising alamarBlue. Methods: Compounds containing Schiff bases (a-d) and both Schiff bases and morpholine rings (e-h) were tested. Compounds were diluted in the range of 20000-39 µg/mL. L. infantum promastigotes were added to the wells, which were then incubated at 27 °C. The proliferation of Leishmania promastigotes was evaluated after 24, 48 and 72 hours. Results: In this study, compounds b, c and d (MIC values 156 µg/mL, 78 µg/mL and 156 µg/mL) were found to be effective against L. infantum promastigotes, whereas compound f (MIC >20000 µg/mL) was found to be more the most ineffective compound. Conclusion: These compounds may be potential drug candidates for the treatment of leishmaniasis. According to the results, there is a need for further studies, such as in vivo experimental animal models and ex vivo Leishmania amastigote macrophage cultures for compounds showing antileishmanial effects.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Morfolinas/farmacologia , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Leishmania infantum/crescimento & desenvolvimento , Bases de Mannich , Morfolinas/química , Testes de Sensibilidade Parasitária , Bases de Schiff
11.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348757

RESUMO

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b-6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Bases de Mannich/química , Oxidiazóis/química , Piridazinas/farmacologia , Pirróis/farmacologia , Antioxidantes/síntese química , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Feminino , Fibroblastos/metabolismo , Humanos , Concentração Inibidora 50 , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Pirróis/síntese química , Pirróis/química , Soroalbumina Bovina/química , Relação Estrutura-Atividade
12.
Nat Commun ; 11(1): 5372, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097724

RESUMO

Chiral aldehyde catalysis is a burgeoning strategy for the catalytic asymmetric α-functionalization of aminomethyl compounds. However, the reaction types are limited and to date include no examples of stereodivergent catalysis. In this work, we disclose two chiral aldehyde-catalysed diastereodivergent reactions: a 1,6-conjugate addition of amino acids to para-quinone methides and a bio-inspired Mannich reaction of pyridinylmethanamines and imines. Both the syn- and anti-products of these two reactions can be obtained in moderate to high yields, diastereo- and enantioselectivities. Four potential reaction models produced by DFT calculations are proposed to explain the observed stereoselective control. Our work shows that chiral aldehyde catalysis based on a reversible imine formation principle is applicable for the α-functionalization of both amino acids and aryl methylamines, and holds potential to promote a range of asymmetric transformations diastereoselectively.


Assuntos
Aldeídos/química , Aminas/química , Aminoácidos/química , Iminas/química , Catálise , Indolquinonas/química , Bases de Mannich/química , Metilaminas/química , Estrutura Molecular , Estereoisomerismo
13.
Drug Des Devel Ther ; 14: 4477-4492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33122891

RESUMO

Purpose: A new series of tetrazole derivatives, which are renowned antimicrobials possessing a five-membered aromatic heterocyclic group, are synthesized herein and subjected to antimicrobial and cytotoxicity screening. Methods: The tetrazole derivatives were synthesized via ultrasonication using Mannich base condensation. Structural verification of the products was performed using IR, 1H NMR, and 13C NMR spectroscopy, as well as mass spectroscopic and elemental analyses. The compounds were then screened for antimicrobial and cytotoxic activity against HepG2 (liver), MCF-7 (breast), and HeLa (cervical) cell lines. Inter- and intra-molecular binding interactions were determined using molecular docking studies. The exact binding mode between the most active tetrazole derivatives (ie, 1b, 2a, and 2b) and the proteins (ie, 4OR7, 1AI9, and 4FM9) was established using Autodock Vina 1.1.2 software and compared to the binding mode of the reference compounds (ie, cefazolin, clotrimazole, and fluorouracil). Results: Compound 1b was extremely active against Enterococcus faecalis relative to the positive control cefazolin. Compounds 1b and 1e were active against Candida albicans and Microsporum audouinii compared to the positive control clotrimazole in antifungal screening. The HepG2 (liver) and MCF-7 (breast) cancer cell lines were particularly susceptible to the synthesized compounds. Compared to the control compound fluorouracil, 2a and 2b were extremely active against all three cancer cell lines. Molecular docking studies showed that 2b exhibited higher binding affinity (-7.8 kcal/mol) to the 4OR7 protein than the control cefazolin (-7.2 kcal/mol). Conclusion: Generally, 1b, 2a, and 2b exhibited impressive inhibitory capabilities in antibacterial, antifungal, and cytotoxic screenings relative to the reference compounds. The results of the molecular docking studies and both the microbial and anticancer screenings indicate that these novel derivatives could be developed into potential therapeutic agents for medical applications.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Tetrazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Bases de Mannich/química , Bases de Mannich/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
14.
ACS Infect Dis ; 6(9): 2478-2489, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32786272

RESUMO

Dunnianol, a natural sesqui-neoligan derived from the leaves and stems of Illicium simonsii Maxim, has been found to possess moderate antibacterial activity. To improve the antibacterial activity and solubility of dunnianol, a series of dunnianol-based Mannich bases were prepared and evaluated for their antibacterial activities. The most promising compound, 5a', exhibited excellent antibacterial activity against Staphylococcus aureus and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1 to 2 µg/mL. Structure-activity relationships indicated that the introduction of (dimethylamino)methyl at the ortho position of the phenolic hydroxyl group of dunnianol could obtain a more active compound. A mechanism study revealed that 5a' killed MRSA more rapidly than did vancomycin by disrupting the cell membrane. Moreover, 5a' was not susceptible to drug resistance development and also showed low toxicity and good antibacterial efficacy in vivo. These results indicate that the dunnianol-based Mannich base 5a' could be a promising antibiotic candidate for further research.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Bases de Mannich/farmacologia , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina
15.
Bioorg Med Chem Lett ; 30(17): 127348, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738996

RESUMO

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure-activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites. Efforts were made to modify the phenolic Mannich base functionality of 1, to prevent formation of a reactive quinone methide. Homologated analog 28 had reduced potency relative to 1, but still inhibited growth with EC50 ≤ 200 nM. Thus, the antimalarial activity of 1 does not derive from quinone methide formation. Chemical stability studies on dimethyl analog 2 showed remarkable hydrolytic stability of both the phenolic Mannich base and ethyl ester moieties, and 1 was evaluated for in vivo efficacy in P. berghei-infected mice (40 mg/kg, oral). Unfortunately, no reduction in parasitemia was seen relative to control. These results are discussed in the context of measured plasma and hepatocyte stabilities, with reference to structurally-related, orally-efficacious antimalarials.


Assuntos
Antimaláricos/farmacologia , Bases de Mannich/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Malária/tratamento farmacológico , Malária/parasitologia , Bases de Mannich/farmacologia , Bases de Mannich/uso terapêutico , Camundongos , Plasmodium berghei/patogenicidade
16.
Eur J Med Chem ; 205: 112663, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791403

RESUMO

Magnolol, a natural bioactive neolignan, was found in the bark of a traditional Chinese medicine Magnoliae officinalis ("Hou Po" in Chinese). In this study, thrity-two magnolol-based Mannich base derivatives 3a-p and 4a-p were synthesized, and evaluated for their anti-proliferative activities against a panel of human tumor cell lines (T47D, MCF-7, Hela and A549). Among all derivatives, compound 3p displayed the most potent antiproliferative activity against T47D, MCF-7 and Hela cell lines with IC50 values of 0.91, 3.32 and 1.71 µM, respectively. Compared with the parental magnolol and the positive drug cisplatin, 3p exhibited up to 76.1-fold and 10.3-fold enhancement of cytotoxic effect on T47D cancer cells, respectively. Mechanism study revealed that the most potent derivative 3p suppressed cancer cells via inducing autophagy. Moreover, 3p also possessed suppressive effects on migration of T47D and Hela cancer cells. In addition, some interesting structure-activity relationships (SARs) were also summarized.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Lignanas/síntese química , Lignanas/farmacologia , Antineoplásicos/química , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Lignanas/química , Bases de Mannich/química , Relação Estrutura-Atividade
17.
Molecules ; 25(11)2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545290

RESUMO

Mankind has always suffered from multiple diseases. Therefore, there has been a rigorous need in the field of medicinal chemistry for the design and discovery of new and potent molecular entities. In this work, thirteen tetrahydroquinoline derivatives were synthesized and evaluated biologically for their antioxidant, α-amylase enzyme inhibitory, anti-proliferative and anti-inflammatory activities. SF8 showed the lowest IC50 of 29.19 ± 0.25 µg/mL by scavenging DPPH free radicals. SF5 showed significant antioxidant activity in total antioxidant capacity (TAC) and total reducing power (TRP) assays. SF5 and SF9 showed the maximum inhibition of α-amylase enzyme i.e., 97.47% and 89.93%, respectively, at 200 µg/mL concentration. Five compounds were shortlisted to determine their anti-proliferative potential against Hep-2C cells. The study was conducted for 24, 48 and 72 h. SF8 showed significant results, having an IC50 value of 11.9 ± 1.04 µM at 72 h when compared with standard cisplatin (IC50 value of 14.6 ± 1.01 µM). An in vitro nitric oxide (NO) assay was performed to select compounds for in vivo anti-inflammatory activity evaluation. SF13 scavenged the NO level to a maximum of 85% at 50 µM concentration, followed by SF1 and SF2. Based on the NO scavenging assay results, in vivo anti-inflammatory studies were also performed and the results showed significant activity compared to the standard, acetylsalicylic acid (ASA).


Assuntos
Anti-Inflamatórios/síntese química , Antineoplásicos/síntese química , Antioxidantes/síntese química , Edema/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Quinolinas/síntese química , Administração Oral , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Aspirina/farmacologia , Carragenina/efeitos adversos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Modelos Animais de Doenças , Edema/induzido quimicamente , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Bases de Mannich , Camundongos , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , alfa-Amilases/antagonistas & inibidores
18.
Mol Cell Biochem ; 471(1-2): 29-39, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32472321

RESUMO

P53 plays an important role in maintaining genetic stability and development of resistance against tumors. Dysregulation of P53 gene is one of the key factors contributing to the etiology of neuroblastoma which causes cells to evade apoptosis. Activating P53 pathway can be a therapeutic alternative to the currently available medicinal strategies. Mannich bases have been known to possess various biological activities including the anticancer activity. In this study, we have targeted the P53 pathway by novel Mannich base (3FB3FA8H) which can be a future prospect to cure neuroblastoma. 3FB3FA8H has shown modulation of P53 pathway leading to apoptosis of neuroblastoma cells. Mitochondrial membrane permeability is also increased by 3FB3FA8H which may be a consequence of P53 pathway modulation. 3FB3FA8H increases the mRNA levels of P53 leading to activation of BAX. Inclining BAX/BCL2 ratio towards apoptotic BAX leads to cleavage of caspase 3, ultimately, causing apoptosis. Series of experiments provide the evidence that Mannich base 3FB3FA8H leads to P53-mediated apoptosis. Inducing apoptosis by this mechanism could be of central importance in reducing tumor burden which can be a good prospect for neuroblastoma patients.


Assuntos
Antineoplásicos/farmacologia , Fluorbenzenos/farmacologia , Hidroxiquinolinas/farmacologia , Bases de Mannich/farmacologia , Neuroblastoma/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Bioorg Chem ; 100: 103892, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32388433

RESUMO

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated invivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Edema/tratamento farmacológico , Naproxeno/uso terapêutico , Dor/tratamento farmacológico , Triazóis/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Edema/metabolismo , Humanos , Masculino , Bases de Mannich , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naproxeno/análogos & derivados , Naproxeno/síntese química , Dor/metabolismo , Triazóis/síntese química , Triazóis/química
20.
ACS Infect Dis ; 6(7): 1882-1893, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32413266

RESUMO

Chemistry campaigns identified amphiphilic indolyl Mannich bases as novel membrane-permeabilizing antimycobacterials. Spiroketal analogs of this series showed increased potency, and the lead compound 1 displayed efficacy in a mouse model of tuberculosis. Yet the mechanism by which the spiroketal moiety accomplished the potency "jump" remained unknown. Consistent with its membrane-permeabilizing mechanism, no resistant mutants could be isolated against indolyl Mannich base 2 lacking the spiroketal moiety. In contrast, mutations resistant against spiroketal analog 1 were obtained in mycobacterial membrane protein large 3 (MmpL3), a proton motive force (PMF)-dependent mycolate transporter. Thus, we hypothesized that the potency jump observed for 1 may be due to MmpL3 inhibition acquired by the addition of the spiroketal moiety. Here we showed that 1 inhibited MmpL3 flippase activity without loss of the PMF, colocalized with MmpL3tb-GFP in intact organisms, and yielded a consistent docking pose within the "common inhibitor binding pocket" of MmpL3. The presence of the spiroketal motif in 1 ostensibly augmented its interaction with MmpL3, an outcome not observed in the nonspiroketal analog 2, which displayed no cross-resistance to mmpL3 mutants, dissipated the PMF, and docked poorly in the MmpL3 binding pocket. Surprisingly, 2 inhibited MmpL3 flippase activity, which may be an epiphenomenon arising from its wider membrane disruptive effects. Hence, we conclude that the potency increase associated with the spiroketal analog 1 is linked to the acquisition of a second mechanism, MmpL3 inhibition. In contrast, the nonspiroketal analog 2 acts pleiotropically, affecting several cell membrane-embedded targets, including MmpL3, through its membrane permeabilizing and depolarizing effects.


Assuntos
Mycobacterium tuberculosis , Ácidos Micólicos , Animais , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Furanos , Bases de Mannich , Proteínas de Membrana/genética , Camundongos , Mycobacterium tuberculosis/genética , Compostos de Espiro
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