RESUMO
A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Janus Quinases , Purinas/farmacologia , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
BACKGROUND: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths. INTRODUCTION: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed. METHODS: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors. RESULTS: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays. CONCLUSION: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays.
Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleotidiltransferases/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Nucleotidiltransferases/metabolismoRESUMO
Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC50 values of 0.64-51.09 µM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC50 (0.64 µM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Hidrazonas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Desenho de Fármacos , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Indanos/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure-activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G0/G1 cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofenantridinas/química , Benzofenantridinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Capsaicina/síntese química , Capsaicina/farmacologia , Desenho Assistido por Computador , Desenho de Fármacos , Simulação de Dinâmica Molecular , Animais , Capsaicina/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Análise de Componente Principal , Relação Estrutura-AtividadeRESUMO
In the title compound, C16H15NO3, the five-membered 1,3-dioxole ring is in an envelope conformation with the methyl-ene C atom as the flap atom [lying 0.202â (3)â Å out of the plane formed by the other four atoms]. The benzene ring makes a dihedral angle of 84.65â (4)° with the best least-squares plane through the 1,3-benzodioxole fused-ring system, which substitutes the 2-methoxyphenol moiety in capsaicin. In the crystal, mol-ecules are connected into a zigzag supra-molecular chain along the c-axis direction by N-Hâ¯O hydrogen bonds. These chains are connected into a layer in the ac plane by C-Hâ¯π inter-actions.
RESUMO
The title compound, C14H13NO4S, an analogue of capsaicin, differs from the latter by having a 1,3-benzodioxole ring rather than a 2-meth-oxy-phenol moiety, and having a benzene-sulfonamide group instead of an aliphatic amide chain. The five-membered ring is in an envelope conformation with the methyl-ene C atom lying 0.221â (6)â Å out of the plane formed by the other four atoms. The dihedral angle between the phenyl ring and the mean plane of the 1,3-benzodioxole fused-ring system is 84.65â (4)°. In the crystal, mol-ecules aggregate into supra-molecular layers in the ac plane through C-Hâ¯O, N-Hâ¯O and C-Hâ¯π inter-actions.