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1.
J Enzyme Inhib Med Chem ; 38(1): 2169682, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36688444

RESUMO

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1ß and NO. In addition, compound 3f presented significant neuroprotective effect on Aß25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl3-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.


Assuntos
Doença de Alzheimer , Hidroxiquinolinas , Fármacos Neuroprotetores , Quinolinas , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Carbamatos/farmacologia , Peixe-Zebra , Inibidores da Colinesterase/farmacologia , Quinolinas/farmacologia , Desenho de Fármacos , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular
2.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232533

RESUMO

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 µM and 28.37 ± 1.85 µM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 µM and 6.05 ± 1.17 µM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 µM). It is worth noting that 3-aminoquinoline derivatives 12a-12d exhibited better drug-like properties.


Assuntos
Doença de Alzheimer , Hidroxiquinolinas , Acetilcolinesterase/metabolismo , Aminas/farmacologia , Aminoquinolinas/farmacologia , Benzotiazóis , Carbono , Inibidores da Colinesterase/farmacologia , Galantamina , Humanos , Cinética , Simulação de Acoplamento Molecular , Morfolinas , Relação Estrutura-Atividade , Ácidos Sulfônicos
3.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234741

RESUMO

Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Quinolinas , Antineoplásicos/química , Apoptose , Benzoquinonas , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Histonas , Humanos , Hidroxiquinolinas/farmacologia , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxigênio/metabolismo , Quinolinas/química , Quinonas/metabolismo , Quinonas/farmacologia , Estreptonigrina , Proteína Supressora de Tumor p53 , Proteína X Associada a bcl-2/metabolismo
4.
Acta Chim Slov ; 69(3): 694-699, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36196828

RESUMO

Two new oxidovanadium(V) complexes, [VOL1(HQ)] (1) and [VOL2(SAH)] (2), were prepared by the reaction of [VO(acac)2] (where acac = acetylacetonate) with N'-(3-ethoxy-2-hydroxybenzylidene)nicotinohydrazide (H2L1) and 8-hydroxyquinoline (HHQ), and N'-(2-hydroxy-4-methoxybenzylidene)nicotinohydrazide (H2L2) and salicylhydroxamic acid (HSAH), respectively, in methanol. Crystal and molecular structures of the complexes were determined by elemental analysis, infrared spectroscopy and single crystal X-ray diffraction. The V atoms in both complexes are in octahedral coordination. Thermal stability of the complexes was studied. Both complexes can decrease the blood glucose level in alloxan-diabetic mice, but the blood glucose level in the treated normal mice was not altered.


Assuntos
Diabetes Mellitus Experimental , Insulinas , Aloxano , Animais , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Hidrazonas/química , Hidroxiquinolinas , Ligantes , Metanol , Camundongos , Oxiquinolina
5.
J Am Chem Soc ; 144(39): 18135-18143, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36137546

RESUMO

The field of anion recognition chemistry is dominated by two fundamental approaches to design receptors. One relies on the formation of covalent bonds resulting in organic and often neutral host species, while the other one utilizes metal-driven self-assembly for the formation of charged receptors with well-defined nanocavities. Yet, the combination of their individual advantages in the form of charge-neutral metal-assembled bench-stable anion receptors is severely lacking. Herein, we present a fluorescent and uncharged double-stranded hydroxyquinoline-based zinc(II) helicate with the ability to bind environmentally relevant dicarboxylate anions with high fidelity in dimethyl sulfoxide (DMSO) at nanomolar concentrations. These dianions are pinned between zinc(II) centers with binding constants up to 145 000 000 M-1. The presented investigation exemplifies a pathway to bridge the two design approaches and combine their strength in one structural motif as an efficient anion receptor.


Assuntos
Dimetil Sulfóxido , Hidroxiquinolinas , Ânions/química , Ácidos Carboxílicos , Metais , Zinco
6.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077085

RESUMO

The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett-Brown substituent were correlated.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Hidroxiquinolinas , Antineoplásicos/farmacologia , Compostos de Benzilideno , Citotoxinas , Doxorrubicina/farmacologia , Humanos
7.
Bioorg Chem ; 127: 105998, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35797861

RESUMO

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 µM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 µM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Neoplasias Ovarianas , Quinolinas , Animais , Antineoplásicos/farmacologia , Autofagia , Proteína 5 Relacionada à Autofagia/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Estrutura Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Relação Estrutura-Atividade
8.
Molecules ; 27(13)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35807279

RESUMO

This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC50 values. It was revealed that compounds 2a, 2b, 2c, and 2q displayed a significant inhibition JAK3 (IC50 = 0.36 µM, 0.38 µM, 0.41 µM, and 0.46 µM, respectively); moreover, compounds 2a and 2b displayed excellent activities against NPM1-ALK (IC50 = 0.54 µM, 0.25 µM, respectively), against cRAF[Y340D][Y341D], compound 2c showed excellent activity, and compound 2q showed weak activity (IC50 = 0.78 µM, 5.34 µM, respectively) (sorafenib IC50 = 0.78 µM, 0.43 µM, 1.95 µM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Quinolinas , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/química , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Tionas
9.
J Org Chem ; 87(10): 6794-6806, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35512011

RESUMO

The ability of long-range proton transport by substitution of 7-hydroxyquinoline at the eighth position with sulfonamide and sulfonylhydrazone rotor units to act as a crane-arm has been studied. Different proton transport pathways triggered by different stimuli have been established depending on the structure of the crane-arms. Solvent-driven proton switching from OH to the quinoline nitrogen (Nquin) site, facilitated by a sulfonamide transporter group in polar protic and aprotic solvents, has been confirmed by optical (absorption and fluorescence) and NMR spectroscopies as well as by single-crystal X-ray structure analysis. Photoinduced long-range proton transport to the Nquin site upon 340 nm UV light irradiation has been estimated in sulfonylhydrazone, which is not sensitive to solvent-driven switching. Both compounds have exhibited acid-triggered switching by trifluoroacetic acid due to the formation of a stable six-membered intramolecular hydrogen bonding interaction between the protonated Nquin and crane-arm. The structures of acid-switched form were confirmed by NMR spectroscopy and single-crystal X-ray structure analysis. The behavior of the compounds suggests a big step forward in the advanced proton pump-switching architecture because they cover three distinct driving forces in the switching process: solvent, light, and acid.


Assuntos
Hidroxiquinolinas , Prótons , Ligação de Hidrogênio , Hidroxiquinolinas/química , Quinina , Solventes/química , Sulfonamidas
10.
Eur J Med Chem ; 238: 114434, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35551038

RESUMO

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 µM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound 1l indicated a higher potency than sorafenib against 53 of tested cancer cell lines. Compounds 1j-l demonstrated promising selectivity against cancer cells than normal cells. Moreover, compound 1l induced apoptosis and necrosis in RPMI-8226 cell line in a dose-dependent manner. In addition, compounds 1j-l were tested against C-RAF kinase as a potential molecular target. The three compounds showed high potency, and the most potent C-RAF kinase inhibitor was compound 1j with an IC50 value of 0.067 µM. In addition, Compounds 1j-l were further tested at 1 µM concentration against a panel of another twelve kinases and they showed a high selectivity for C-RAF kinase. Molecular modeling studies were performed to illuminate on the putative binding interactions of these motifs in the active site of C-RAF kinase. Additional studies were conducted to measure aqueous solubility, partition coefficient, and Caco-2 permeability of the most promising derivatives.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Quinolinas , Antineoplásicos/química , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxiquinolinas/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-raf/farmacologia , Quinolinas/química , Sorafenibe/farmacologia , Relação Estrutura-Atividade
11.
J Med Chem ; 65(6): 5134-5148, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35255688

RESUMO

Twelve new complexes Cu(L1)2-Cu(L12)2 were designed and synthesized to improve their chemotherapeutic properties. They showed considerable antiproliferative activity against T24 cancer cells but lower cytotoxicity to human normal cells HL-7702 and WI-38. A mechanism study indicated that Cu(L4)2 and Cu(L10)2 were reduced to Fenton-like Cu+ by glutathione depletion, and the resulting Cu+ catalyzed the generation of highly toxic hydroxyl radicals from excess H2O2. Simultaneously, Cu(L4)2 and Cu(L10)2 could decrease the catalase activity to restrain H2O2 transfer to H2O for enhanced chemodynamic therapy (CDT). These induced mitochondrial dysfunctions and endoplasmic reticulum stress to induce T24 cell apoptosis. In addition, Cu(L4)2 and Cu(L10)2 inhibited autophagy flux to promote cell apoptosis. Cu(L4)2 and Cu(L10)2 demonstrated strong tumor inhibition ability in the T24 xenograft model. Moreover, Cu(L10)2 showed higher antitumor activity and a better safety profile than the CDT agent Cu1. Cu(L10)2 exhibited excellent pharmacokinetic properties. Collectively, Cu(L4)2 and Cu(L10)2 could be developed as potential CDT candidates for cancer treatment.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Neoplasias , Quinolinas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Linhagem Celular Tumoral , Cobre , Glutationa , Humanos , Peróxido de Hidrogênio/farmacologia , Neoplasias/tratamento farmacológico , Bases de Schiff/farmacologia
12.
Chem Commun (Camb) ; 58(22): 3677-3680, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35225322

RESUMO

A highly enantioselective and regioselective dearomative borylation of 4-quinolinols was developed using a Cu(I)/(R,R)-Ph-BPE catalyst for efficient synthesis of unprecedented heterocyclic α-amino boronates, a new class of compounds potentially relevant to drug discovery, in generally excellent yields and enantioselectivities. The products were also useful intermediates for highly functionalized tetrahydroquinolines and cyclic α-aminoboronate derivatives.


Assuntos
Cobre , Hidroxiquinolinas , Catálise , Estereoisomerismo
13.
Bioorg Chem ; 121: 105671, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35168120

RESUMO

In our efforts to identify novel chemical scaffolds for the development of antimalarial agents, a series of quinoline - imidazole hybrid compounds were synthesized and their blood-stage antimalarial activity was evaluated in both drug-sensitive and -multi drug-resistant (MDR) P. falciparum strains. The new analogs possess sub-micromolar activities against Plasmodium falciparum. Among all synthesized derivatives, 11(xxxii) exhibited significant antimalarial efficacy in-vitro against both CQ-sensitive (IC50-0.14 µM) and MDR strain (IC50- 0.41 µM) with minimal cytotoxicity and high selectivity. Structure-activity relationships revealed that Br and OMe substitutions on quinoline ring improved the antimalarial activity and selectivity index. The role of stereochemistry in the inhibitory activity was assessed by enantiomeric separation of a racemic mixture of 11(xxxii). The enantiomer (-)-11(xxxii) had potent antimalarial activity over the other isomer, with IC50 of 0.10 µM.


Assuntos
Antimaláricos , Antiprotozoários , Hidroxiquinolinas , Nitroimidazóis , Quinolinas , Inibidores de 14-alfa Desmetilase/farmacologia , Antimaláricos/química , Antiprotozoários/farmacologia , Inibidores do Citocromo P-450 CYP3A , Imidazóis , Plasmodium falciparum , Quinolinas/química , Relação Estrutura-Atividade
14.
ChemMedChem ; 17(5): e202100714, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-34978160

RESUMO

Due to the ever-increasing antimicrobial resistance there is an urgent need to continuously design and develop novel antimicrobial agents. Inspired by the broad antibacterial activities of various heterocyclic compounds such as 2-quinolone derivatives, we designed and synthesized new methyl-(2-oxo-1,2-dihydroquinolin-4-yl)-L-alaninate-1,2,3-triazole derivatives via 1,3-dipolar cycloaddition reaction of 1-propargyl-2-quinolone-L-alaninate with appropriate azide groups. The synthesized compounds were obtained in good yield ranging from 75 to 80 %. The chemical structures of these novel hybrid molecules were determined by spectroscopic methods and the antimicrobial activity of the compounds was investigated against both bacterial and fungal strains. The tested compounds showed significant antimicrobial activity and weak to moderate antifungal activity. Despite the evident similarity of the quinolone moiety of our compounds with fluoroquinolones, our compounds do not function by inhibiting DNA gyrase. Computational characterization of the compounds shows that they have attractive physicochemical and pharmacokinetic properties and could serve as templates for developing potential antimicrobial agents for clinical use.


Assuntos
Anti-Infecciosos , Quinolonas , Antibacterianos/química , Anti-Infecciosos/farmacologia , Antifúngicos/química , Hidroxiquinolinas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolonas/farmacologia , Relação Estrutura-Atividade , Triazóis/química
15.
Life Sci ; 293: 120272, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35065164

RESUMO

Carbostyrils are quinolone derivatives, with possible growth inhibition properties on cancer cells. Unlike many tumors, 15-Lipoxygenase-1 (15-LOX-1) is highly expressed in prostate cancer (PCa) cells and has oncogenic properties. Here, with the hypothesis that 6-, 7- and 8-geranyloxycarbostyril (GQ) have inhibitory properties on 15-LOX-1, their effects were assessed on PCa cells. Their cytotoxic effects were evaluated by MTT assay and mechanism of cell death was investigated using annexin V/PI staining. Finally, the anti-tumor properties of 8-GQ were assessed in immunocompromised C57BL/6 mice bearing human PCa cells. Accordingly, these compounds could effectively inhibit 15-LOX activity in PCa cells. MTT and flow cytometry tests confirmed their toxic effects on PCa cells, with no significant toxicity on normal cells, and apoptosis was the main mechanism of cell death. In vivo results indicated that use of 8-GQ at 50 mg/kg had stronger anti-tumor effects than 5 mg/kg cisplatin, with fewer side effects on normal tissues. Therefore, 8-GQ can be introduced as a potential drug candidate with 15-LOX-1 inhibitory potency, which can be effective in treatment of prostate cancer, and should be considered for further drug screening investigations.


Assuntos
Antineoplásicos/uso terapêutico , Araquidonato 15-Lipoxigenase/metabolismo , Hidroxiquinolinas/uso terapêutico , Inibidores de Lipoxigenase/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Quinolonas/uso terapêutico , Animais , Antineoplásicos/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Hidroxiquinolinas/química , Inibidores de Lipoxigenase/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/patologia , Quinolonas/química , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
J Inorg Biochem ; 228: 111697, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34999425

RESUMO

In this study, four hybrid organic-inorganic compounds (8-H2Q)2[PdCl4] (1), (H2ClQ)2[PdCl4] (2), (H2NQ)2[PdCl4] (3) and (H2MeQ)2[PdCl4]·2H2O (4) (where 8-H2Q = 8-hydroxyquinolinium, H2ClQ = 5-chloro-8-hydroxyquinolinium, H2NQ = 5-nitro-8-hydroxyquinolinium and H2MeQ = 2-methyl-8-hydroxyquinolinium) were synthesized through organic cation modulation. Single-crystal X-ray structure analysis of compounds 1 and 3 indicates that their structures are planar and consist of [PdCl4]2- anions and 8-H2Q or H2NQ cations, respectively. Both ionic components are held together through ionic interactions and hydrogen bonds forming infinite chains linked through π-π interactions to form 2D structures. Furthermore, NMR spectroscopy, UV-Vis spectroscopy, elemental analysis, and FT-IR spectroscopy were used to explore the synthesized compounds. The DNA interaction, antimicrobial activity, antiproliferative activity, and radical scavenging effect of the compounds were evaluated. The hybrid compounds and their free ligands can interact with the calf thymus DNA via an intercalation mode involving the insertion of the aromatic chromophore between the base pairs of DNA; compound 1 has the highest binding affinity. Moreover, they have high antimicrobial efficacy against the tested 14 strains of microorganisms with minimum inhibitory concentration values ranging from <1.95 to 250 µg/mL. The antiproliferative activity of the compounds was investigated against three different cancer cell lines, and their selectivity was verified on mesenchymal stem cells. Compounds 1 and 2 displayed selective and high cytotoxicity against human lung and breast cancer cells and showed moderate cytotoxicity against colon cancer cells. Accordingly, they might be auspicious candidates for future pharmacological investigations in lung and breast cancer research.


Assuntos
Complexos de Coordenação/química , Hidroxiquinolinas/química , Paládio/química , Compostos de Quinolínio/química , Células A549 , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Quelantes/química , Cristalografia por Raios X/métodos , DNA/química , Sequestradores de Radicais Livres/química , Células HCT116 , Humanos , Hidroxiquinolinas/síntese química , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Compostos de Quinolínio/síntese química , Espécies Reativas de Oxigênio/metabolismo
17.
J Biomol Struct Dyn ; 40(18): 8464-8493, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34032180

RESUMO

The COVID-19 pandemic infection has claimed many lives and added to the social, economic, and psychological distress. The contagious disease has quickly spread to almost 218 countries and territories following the regional outbreak in China. As the number of infected populations increases exponentially, there is a pressing demand for anti-COVID drugs and vaccines. Virtual screening provides possible leads while extensively cutting down the time and resources required for ab-initio drug design. We report structure-based virtual screening of a hundred plus library of quinoline drugs with established antiviral, antimalarial, antibiotic or kinase inhibitor activity. In this study, targets having a role in viral entry, viral assembly, and viral replication have been selected. The targets include: 1) RBD of receptor-binding domain spike protein S 2) Mpro Chymotrypsin main protease 3) Ppro Papain protease 4) RNA binding domain of Nucleocapsid Protein, and 5) RNA Dependent RNA polymerase from SARS-COV-2. An in-depth analysis of the interactions and G-score compared to the controls like hydroxyquinoline and remdesivir has been presented. The salient results are (1) higher scoring of antivirals as potential drugs (2) potential of afatinib by scoring as better inhibitor, and (3) biological explanation of the potency of afatinib. Further MD simulations and MM-PBSA calculations showed that afatinib works best to interfere with the the activity of RNA dependent RNA polymerase of SARS-COV-2, thereby inhibiting replication process of single stranded RNA virus. Communicated by Ramaswamy H. Sarma.


Assuntos
Antimaláricos , Hidroxiquinolinas , Quinolinas , Afatinib , Antibacterianos , Antivirais/química , Quimotripsina , Humanos , Simulação de Acoplamento Molecular , Proteínas do Nucleocapsídeo , Pandemias , Papaína , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Quinolinas/farmacologia , RNA Polimerase Dependente de RNA , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus
18.
J Fluoresc ; 32(1): 165-173, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34674114

RESUMO

ß-cyclodextrin-hydroxyquinoline functionalized graphene oxide (GO-CD-HQ) was facilely fabricated to monitor and quantitatively analyze cations in aqueous media. The optical probe was notably selective enhanced toward Pb2+ ions over the other tested ions like Cu2+, Hg2+, Ca2+, Na+, K+, Zn2+, Fe2+, Fe3+, Ag+, Mg2+, and Cd2+ at 468 nm as an emission wavelength. The probe was shown the best performance in pH value, 5, and optimum time 1 min. Absorption spectra have clearly confirmed the static type fluorescence enhancement mechanism of GO-CD-HQ. Under the optimal conditions, the detection limit of it and linear concentration range for Pb2+ ions were obtained as 3.72 × 10-5 M and (5-60) × 10-5 M, respectively. Additionally, the developed assay exhibited logic gate behavior with Pb2+ ions and vitamin C as a masking agent for cited ions.


Assuntos
Ácido Ascórbico , Corantes Fluorescentes , Grafite , Chumbo/análise , Água/química , Concentração de Íons de Hidrogênio , Hidroxiquinolinas , Íons , Limite de Detecção , beta-Ciclodextrinas
19.
Front Immunol ; 12: 680611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956168

RESUMO

Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.


Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Interferon gama/biossíntese , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Umbeliferonas/farmacologia , Acetanilidas/farmacologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Adolescente , Adulto , Aminopiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Hidrazonas/farmacologia , Hidroxiquinolinas/farmacologia , Interferon gama/genética , Interleucina-12/fisiologia , Células K562 , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/fisiologia , Adulto Jovem
20.
PLoS Negl Trop Dis ; 15(11): e0009969, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34793441

RESUMO

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.


Assuntos
Cólera/tratamento farmacológico , Diarreia/tratamento farmacológico , Hidroxiquinolinas/administração & dosagem , Oxidiazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Cólera/metabolismo , Cólera/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Diarreia/metabolismo , Diarreia/microbiologia , Método Duplo-Cego , Feminino , Humanos , Hidroxiquinolinas/efeitos adversos , Masculino , Oxidiazóis/efeitos adversos , Vibrio cholerae/fisiologia , Adulto Jovem
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