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1.
BMC Plant Biol ; 24(1): 364, 2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38702592

RESUMEN

BACKGROUND: This study aimed to investigate the alterations in biochemical and physiological responses of oat plants exposed to antimony (Sb) contamination in soil. Specifically, we evaluated the effectiveness of an arbuscular mycorrhizal fungus (AMF) and olive mill waste (OMW) in mitigating the effects of Sb contamination. The soil was treated with a commercial strain of AMF (Rhizophagus irregularis) and OMW (4% w/w) under two different levels of Sb (0 and 1500 mg kg-1 soil). RESULTS: The combined treatment (OMW + AMF) enhanced the photosynthetic rate (+ 40%) and chlorophyll a (+ 91%) and chlorophyll b (+ 50%) content under Sb condition, which in turn induced more biomass production (+ 67-78%) compared to the contaminated control plants. More photosynthesis in OMW + AMF-treated plants gives a route for phenylalanine amino acid synthesis (+ 69%), which is used as a precursor for the biosynthesis of secondary metabolites, including flavonoids (+ 110%), polyphenols (+ 26%), and anthocyanins (+ 63%) compared to control plants. More activation of phenylalanine ammonia-lyase (+ 38%) and chalcone synthase (+ 26%) enzymes in OMW + AMF-treated plants under Sb stress indicated the activation of phenylpropanoid pathways in antioxidant metabolites biosynthesis. There was also improved shifting of antioxidant enzyme activities in the ASC/GSH and catalytic pathways in plants in response to OMW + AMF and Sb contamination, remarkably reducing oxidative damage markers. CONCLUSIONS: While individual applications of OMW and AMF also demonstrated some degree of plant tolerance induction, the combined presence of AMF with OMW supplementation significantly enhanced plant biomass production and adaptability to oxidative stress induced by soil Sb contamination.


Asunto(s)
Antimonio , Micorrizas , Olea , Contaminantes del Suelo , Micorrizas/fisiología , Olea/microbiología , Contaminantes del Suelo/metabolismo , Antimonio/metabolismo , Adaptación Fisiológica , Residuos Industriales , Fotosíntesis/efectos de los fármacos , Biodegradación Ambiental , Biomasa
2.
Arch Pharm (Weinheim) ; : e2400057, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775630

RESUMEN

Quinazoline and quinazolinone derivatives piqued medicinal chemistry interest in developing novel drug candidates owing to their pharmacological potential. They are important chemicals for the synthesis of a variety of physiologically significant and pharmacologically useful molecules. Quinazoline and quinazolinone derivatives have anticancer, anti-inflammatory, antidiabetic, anticonvulsant, antiviral, and antimicrobial potential. The increased understanding of quinazoline and quinazolinone derivatives in biological activities provides opportunities for new medicinal products. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, structure-activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives to help in the development of new quinazoline and quinazolinone derivatives.

3.
Saudi Pharm J ; 32(1): 101913, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38204591

RESUMEN

To fully evaluate and define the new drug molecule for its pharmacological characteristics and toxicity profile, pre-clinical and clinical studies are conducted as part of the drug research and development process. The average time required for all drug development processes to finish various regulatory evaluations ranges from 11.4 to 13.5 years, and the expense of drug development is rising quickly. The development in the discovery of newer novel treatments is, however, largely due to the growing need for new medications. Methods to identify Hits and discovery of lead compounds along with pre-clinical studies have advanced, and one example is the introduction of computer-aided drug design (CADD), which has greatly shortened the time needed for the drug to go through the drug discovery phases. The pharmaceutical industry will hopefully be able to address the present and future issues and will continue to produce novel molecular entities (NMEs) to satisfy the expanding unmet medical requirements of the patients as the success rate of the drug development processes is increasing. Several heterocyclic moieties have been developed and tested against many targets and proved to be very effective. In-depth discussion of the drug design approaches of newly found drugs from 2020 to 2022, including their pharmacokinetic and pharmacodynamic profiles and in-vitro and in-vivo assessments, is the main goal of this review. Considering the many stages these drugs are going through in their clinical trials, this investigation is especially pertinent. It should be noted that synthetic strategies are not discussed in this review; instead, they will be in a future publication.

4.
Neurochem Res ; 2023 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-37814132

RESUMEN

Chalcones (trans-1,3-diphenyl-2-propen-1-ones) form simple chemical structures that act as precursors for the biogenesis of flavonoids. These are distributed in plants and have two aromatic or heteroaromatic rings connected by a three-carbon α, ß-unsaturated carbonyl group. Considering the importance of chalcones as monoamine oxidase and acetylcholinesterase inhibitors, the study was designed as a comprehensive and systematic analysis to evaluate the pharmacological activities leading to the formation of drug molecules against Alzheimer's disease (AD). Based on our previous research, 11 indolyl chalcones (IC1-IC11) were synthesised and investigated for MAO-B inhibitory activity. The inhibitory potential was evaluated based on binding and reversibility studies using purified enzymes. The active and most promising molecule, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9), also found predominant acetylcholinesterase inhibition and hence it was found dual acting in vitro. Based on this, the molecule IC9 was further subjected to cell line studies to further explore its role as a neuroprotective agent against neuronal degeneration, one of the main contributing parameters related to AD.

5.
Crit Rev Food Sci Nutr ; 63(29): 10217-10229, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-35549783

RESUMEN

This review article depicts the possible replacement of staple cereal sources with some pseudocereals like Chia, Quinoa, Buckwheat, and Amaranth, which not only provide recommended daily allowance of all nutrients but also help to reduce the chances of many non-communicable infections owing to the presence of several bioactive compounds. These pseudocereals are neglected plant seeds and should be added in our routine diet. Besides, they can serve as nutraceuticals in combating various diseases by improving the health status of the consumers. The bioactive compounds like rutin, quercetin, peptide chains, angiotensin I, and many other antioxidants present in these plant seeds help to reduce the oxidative stress in the body which leads toward better health of the consumers. All these pseudocereals have high quantity of soluble fiber which helps to regulate bowel movement, control hypercholesterolemia (presence of high plasma cholesterol levels), hypertension (high blood pressure), and cardiovascular diseases. The ultimate result of consumption of pseudocereals either as a whole or in combination with true cereals as staple food may help to retain the integrity of the human body which increases the life expectancy by slowing down the aging process.


Asunto(s)
Grano Comestible , Semillas , Humanos , Semillas/química , Grano Comestible/química , Antioxidantes/análisis , Suplementos Dietéticos , Dieta
6.
Bioorg Chem ; 133: 106404, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36812829

RESUMEN

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.


Asunto(s)
Antineoplásicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Triazoles/farmacología , Triazoles/química , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
7.
J Enzyme Inhib Med Chem ; 38(1): 246-266, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36458373

RESUMEN

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a-e, and 5a-e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Indoles , Sustancias Protectoras , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/farmacología , Indoles/farmacología , Estómago , Animales , Sustancias Protectoras/farmacología , Antibacterianos/farmacología
8.
J Enzyme Inhib Med Chem ; 38(1): 2250575, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37649381

RESUMEN

In this study, new benzothiazole-pyrimidine hybrids (5a-c, 6, 7a-f, and 8-15) were designed and synthesised. Two different functionalities on the pyrimidine moiety of lead compound 4 were subjected to a variety of chemical changes with the goal of creating various functionalities and cyclisation to further elucidate the target structures. The potency of the new molecules was tested against different tuberculosis (TB) strains. The results indicated that compounds 5c, 5b, 12, and 15 (MIC = 0.24-0.98 µg/mL) are highly active against the first-line drug-sensitive strain of Mycobacterium tuberculosis (ATCC 25177). Thereafter, the anti-tubercular activity was evaluated against the two drug-resistant TB strains; ATCC 35822 and RCMB 2674, where, many compounds exhibited good activity with MIC = 0.98-62.5 3 µg/mL and 3.9-62.5 µg/mL, respectively. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95 µg/mL for MDR TB, and showing the MIC = 3.9 and 7.81 µg/mL for XDR TB, consecutively. Finally, molecular docking studies were performed for the two most active compounds 5c and 15 to explore their enzymatic inhibitory activities.


Asunto(s)
Mycobacterium tuberculosis , Simulación del Acoplamiento Molecular , Benzotiazoles/farmacología , Antihipertensivos , Pirimidinas/farmacología
9.
Arch Pharm (Weinheim) ; 356(7): e2300091, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37021551

RESUMEN

As flavin adenine dinucleotide (FAD)-dependent enzymes, monoamine oxidases (MAOs) catalyze the oxidative deamination of various endogenous and exogenous amines. MAO-A inhibitors are thought to be effective therapeutic agents for treating neurological diseases including depression and anxiety. Due to the academic challenge of developing new human (h) MAO-A inhibitors and the potential for discovering substances with remarkable properties compared to existing MAO-A inhibitors, numerous research groups are looking into novel classes of chemical compounds that may function as selective hMAO-A inhibitors. ß-Carbolines are reported to be a prominent class of bioactive molecules exhibiting MAO-A inhibition. Chemically, ß-carboline is a tricyclic pyrido-3,4-indole ring. It has only recently been discovered that this chemotype has highly effective and specific MAO-A inhibitory activity. In this review, structure-activity relationship studies included in particular research publications from the 1960s to the present are discussed with regard to ß-carboline and its analogs. This comprehensive information helps to design and develop a new family of MAO-A inhibitors for the management of depressive disorders.


Asunto(s)
Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Humanos , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Relación Estructura-Actividad , Monoaminooxidasa/metabolismo , Carbolinas/farmacología , Carbolinas/química
10.
Arch Pharm (Weinheim) ; 356(7): e2300137, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37147779

RESUMEN

Novel thiazolidine-2,4-diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR-2 against HCT-116, MCF-7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF-7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF-7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e-i and 6a-c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR-2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Relación Estructura-Actividad , Línea Celular Tumoral , Tiazolidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptores ErbB/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Simulación del Acoplamiento Molecular , Mutación , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Estructura Molecular
11.
Molecules ; 28(20)2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37894504

RESUMEN

Essential oils are naturally occurring multicomponent combinations of isoprenoids with distinctive odors that are produced by aromatic plants from mevalonic acid. They are extensively applied in aromatherapy for the treatment of various ailments. To investigate the potential therapeutic value of the ingredients in Launaea mucronata essential oil (EO), gas chromatography-mass spectrometry (GC-MS) analysis was used for essential oil characterization. Then, 2,2-diphenyl-1-picrylhydrazyl (DPPH), ß-carotene/linoleic acid, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were used to evaluate the antioxidants. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the cytotoxicity. Following a thorough analysis of the GC-MS chromatogram, 87 components representing 97.98% of the entire EO mixture were identified. N-eicosane (10.92%), 2E,6Z-farnesol (10.74%), and 2Z,6E-farnesyl acetone (46.35%) were determined to be the major components of the oil. When the produced EO was evaluated for its antioxidant properties, it showed a strong inhibitory effect (%) of 65.34 at a concentration of 80 µg/mL. The results (g/mL) showed a positive response against the tested cell lines for HCT-116, MCF-7, and HepG2 (8.45, 10.24, and 6.78 g/mL, respectively). A high-concentration mixture of deadly components consisting of farnesol, bisabolol, eicosane, and farnesyl acetone may be responsible for this significant cytotoxic action, which was especially noticeable in the HepG2 cell line. Molecular docking occurred between farnesol and farnesyl acetone with the target residues of topoisomerases I and II, CDK4/cyclD1, and Aurora B kinases; these showed binding free energies ranging from -4.5 to -7.4 kcal/mol, thus demonstrating their antiproliferative action. In addition, farnesol and farnesyl acetone fulfilled most of the ADME and drug-likeness properties, indicating their activity.


Asunto(s)
Antineoplásicos , Asteraceae , Aceites Volátiles , Aceites Volátiles/farmacología , Aceites Volátiles/química , Antioxidantes/farmacología , Antioxidantes/química , Farnesol , Arabia Saudita , Acetona , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Antineoplásicos/farmacología , Asteraceae/química
12.
Molecules ; 28(16)2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37630420

RESUMEN

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 µM, followed by IHC2 (IC50 = 16.934 µM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 µM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 µM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.


Asunto(s)
Antipsicóticos , Isatina , Neuroblastoma , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Microondas , Simulación del Acoplamiento Molecular , Pargilina , Farmacóforo , Dopaminérgicos , Monoaminooxidasa
13.
Curr Issues Mol Biol ; 44(10): 4490-4499, 2022 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-36286022

RESUMEN

In the search for a new anti-MRSA lead compound, emodin was identified as a good lead against methicillin-resistant Staphylococcus aureus (MRSA). Emodin serves as a new scaffold to design novel and effective anti-MRSA agents. Because rational drug discovery is limited by the knowledge of the drug target, α-hemolysin of Staphylococcus aureus was used in this study because it has an essential role in Staphylococcus infections and because emodin shares structural features with compounds that target this enzyme. In order to explore emodin's interactions with α-hemolysin, all possible ligand binding pockets were identified and investigated. Two ligand pockets were detected based on bound ligands and other reports. The third pocket was identified as a cryptic site after molecular dynamics (MD) simulations. MD simulations were conducted for emodin in each pocket to identify the most plausible ligand site and to aid in the design of potent anti-MRSA agents. Binding of emodin to site 1 was most stable (RMSD changes within 1 Å), while in site 2, the binding pose of emodin fluctuated, and it left after 20 ns. In site 3, it was stable during the first 50 ns, and then it started to move out of the binding site. Site 1 is a possible ligand binding pocket, and this study sheds more light on interaction types, binding mode, and key amino acids involved in ligand binding essential for better lead design. Emodin showed an IC50 value of 6.3 µg/mL, while 1, 6, and 8 triacetyl emodin showed no activity against MRSA. A molecular modeling study was pursued to better understand effective binding requirements for a lead.

14.
Langmuir ; 38(31): 9500-9506, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35900875

RESUMEN

The incorporation of l-ascorbic acid into food products is challenging for food industries due to its chemical instability. This study was conducted to develop a nanoemulsion-based effective colloidal system for the incorporation of l-ascorbic acid (LAA) in functional food products. l-ascorbic acid was encapsulated in nanoemulsions prepared through high-pressure homogenization. The physicochemical characteristics of mixed-surfactant-based LAA nanoemulsions were investigated during storage at different temperatures. The droplet size of LAA nanoemulsions after one month of storage varied in the range of 121.36-150.15 and 121.36-138.25 nm at 25 and 4 °C, respectively. These nanoemulsions remained stable against processing conditions such as heat treatments (10-70 °C), different salt concentrations (40-320 mM), change in pH (3-9), and four freeze-thaw cycles. The temperature and storage intervals have a significant (p < 0.05) effect on the retention of LAA in nanoemulsion-based delivery systems. The findings of this research work have important implications in the designing and preparation of an effective encapsulation system for the inclusion of l-ascorbic acid into functional food products.


Asunto(s)
Ácido Ascórbico , Tensoactivos , Emulsiones , Excipientes , Temperatura
15.
Cell Mol Biol (Noisy-le-grand) ; 67(5): 151-156, 2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35818258

RESUMEN

Antibiotic resistance in pathogenic bacteria to various types of antibiotics has resulted in the necessity of new effective strategies to get around this problem. In recent investigations, metal or metal oxide nanoparticles specifically silver nanoparticles (AgNPs) have been employed successfully to hinder antibiotic-resistant Gram-negative and Gram-positive bacteria. However, AgNPs at high concentrations have cytotoxicity for eukaryotic cells which, application of other biocompatible materials particularly plant secondary metabolites of curcumin and quercetin to reduce cytotoxicity is a critical affair. These compounds may be used directly or indirectly to produce AgNPs. In this regard, modified NPs by curcumin and quercetin have shown an increased therapeutic effect and biocompatibility and biodegredibility properties. Therefore, here, recent advances and challenges about antibacterial and biocompatibility properties of nanoformulation of AgNPs with curcumin and quercetin are presented.


Asunto(s)
Curcumina , Nanopartículas del Metal , Antibacterianos/farmacología , Bacterias , Curcumina/farmacología , Pruebas de Sensibilidad Microbiana , Quercetina/farmacología , Plata/farmacología
16.
Bioorg Chem ; 122: 105752, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35339926

RESUMEN

Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.


Asunto(s)
Antineoplásicos , Leucemia Promielocítica Aguda , Amsacrina/química , Amsacrina/farmacología , Antineoplásicos/química , Apoptosis , Proliferación Celular , ADN-Topoisomerasas de Tipo II/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Topoisomerasa II , Tirosina Quinasa 3 Similar a fms
17.
J Enzyme Inhib Med Chem ; 37(1): 1556-1567, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35635148

RESUMEN

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e, 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e, 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e, 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC50 = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC50 value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC50 value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.


Asunto(s)
Sustancias Intercalantes , Inhibidores de Topoisomerasa II , ADN , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Sustancias Intercalantes/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología
18.
J Enzyme Inhib Med Chem ; 37(1): 986-993, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35322729

RESUMEN

The enormous burden of the COVID-19 pandemic in economic and healthcare terms has cast a shadow on the serious threat of antimicrobial resistance, increasing the inappropriate use of antibiotics and shifting the focus of drug discovery programmes from antibacterial and antifungal fields. Thus, there is a pressing need for new antimicrobials involving innovative modes of action (MoAs) to avoid cross-resistance rise. Thiosemicarbazones (TSCs) stand out due to their easy preparation and polypharmacological application, also in infectious diseases. Recently, we reported a small library of TSCs (1-9) that emerged for their non-cytotoxic behaviour. Inspired by their multifaceted activity, we investigated the antibacterial, antifungal, and antidermatophytal profiles of derivatives 1-9, highlighting a new promising research line. Furthermore, the ability of these compounds to inhibit selected microbial and human carbonic anhydrases (CAs) was assessed, revealing their possible involvement in the MoA and a good selectivity index for some derivatives.


Asunto(s)
Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Hongos/efectos de los fármacos , Tiosemicarbazonas/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Bacterias/enzimología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Hongos/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química
19.
Int J Mol Sci ; 23(18)2022 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-36142887

RESUMEN

Chitosan, a naturally abundant cationic polymer, is chemically composed of cellulose-based biopolymers derived by deacetylating chitin. It offers several attractive characteristics such as renewability, hydrophilicity, biodegradability, biocompatibility, non-toxicity, and a broad spectrum of antimicrobial activity towards gram-positive and gram-negative bacteria as well as fungi, etc., because of which it is receiving immense attention as a biopolymer for a plethora of applications including drug delivery, protective coating materials, food packaging films, wastewater treatment, and so on. Additionally, its structure carries reactive functional groups that enable several reactions and electrochemical interactions at the biomolecular level and improves the chitosan's physicochemical properties and functionality. This review article highlights the extensive research about the properties, extraction techniques, and recent developments of chitosan-based composites for drug, gene, protein, and vaccine delivery applications. Its versatile applications in tissue engineering and wound healing are also discussed. Finally, the challenges and future perspectives for chitosan in biomedical applications are elucidated.


Asunto(s)
Quitosano , Vacunas , Antibacterianos , Biopolímeros/química , Celulosa/química , Quitina/química , Quitosano/química , Bacterias Gramnegativas , Bacterias Grampositivas
20.
Molecules ; 27(9)2022 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-35566313

RESUMEN

Mentha is an aromatic plant used since antiquity for its pharmaceutical virtues. The climate of Saudi Arabia favors the growth of aromatic plants including Mentha suaveolens L. The aim of this study is to analyze the volatile oils of different parts of fresh and dried Mentha suaveolens L. grown in Saudi Arabia (Aljouf area) using Gas Chromatography/Mass Spectrometry (GC/MS) and Gas Chromatography Flame Ionization Detector (GC/FID) techniques, to recognize the effect of drying on chemical composition, then to evaluate the antioxidant and antifungal activities of different extracts. In total, 118 compounds were identified via GC/MS and GC/FID, in which carvone is the main volatile constituent (stems, leaves, whole plant 45-64%). This investigation deduces that Mentha belonged to the carvone chemotype. Then, the analysis of non-volatile constituents of fresh and dried Mentha was performed by HPLC. The main phenolic compound of fresh and dried Mentha for different parts was rosmarinic acid (ranging from 28,002.5 to 6558 µg/g). The ethanolic extract of fresh stem showed the highest antifungal activity (53% inhibition) compared with miconazole (60% inhibition) but the ethanoic extract of dry stem showed no activity. Additionally, all ethanolic extracts, whether for fresh or dry Mentha, have antioxidant activity more than 90% while the antioxidant activity of whole plant volatile oil is equal to 53.33%. This research shows that M. suaveolens L. could be applied to manufacture natural antioxidants, antifungal, and flavoring agents.


Asunto(s)
Mentha , Aceites Volátiles , Antifúngicos/química , Antioxidantes/química , Cromatografía de Gases y Espectrometría de Masas , Mentha/química , Aceites Volátiles/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Arabia Saudita
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