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1.
J Asian Nat Prod Res ; 25(12): 1133-1154, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37066495

RESUMEN

COVID-19, caused by SARS-CoV-2, is spreading worldwide, regardless of different continents, increasing the death toll to almost five million, with more than 300 million reported cases. Researchers have been fighting the greatest threats to human civilization. This report provides a glimpse of ongoing small-molecule research on COVID-19 drugs to save millions of lives, which may provide researchers with a better understanding of rigorously investigated therapeutic agents. This report emphasizes the chemical structures and mechanisms of activity along with drug target information for several small molecules, including marketable drugs and agents under investigation.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Desarrollo de Medicamentos , Antivirales/farmacología
2.
J Org Chem ; 84(14): 8959-8975, 2019 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-31241931

RESUMEN

An efficient palladium(II)-catalyzed cascade reaction of ene-yne substrates carrying cyano/aldehyde group is described. It involves successive hetero- and benz-annulations in one pot via trans-oxo/aminopalladation onto alkyne, followed by 1,2-addition to cyano/aldehyde, providing a convenient synthesis of both naphtho[1,2-b]furans and benzo[g]indoles. The reaction constitutes a fast intramolecular assembly through several carbon-carbon and carbon-heteroatom bond formations taking place in one pot. The reactions are operationally simple, compatible with a range of functional groups and atom-economical in nature.

3.
Org Biomol Chem ; 16(6): 963-980, 2018 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-29340402

RESUMEN

An efficient method has been developed for the stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones 7 through tandem Heck-Suzuki coupling at rt using easily available substrates. DBU easily converted the exocyclic double bond of these compounds to endo, furnishing 8 and 9. Reduction of the carbonyl group of 7 was smoothly carried out with borane dimethyl sulphide. Subsequent treatment with KOtBu provided an easy access to 4-substituted isoquinolines 10a if carried out in refluxing 1,4-dioxane, while reaction in DMF at rt led to the incorporation of an extra hydroxyl group at the benzylic position of the isoquinolines to give 10b. This straightforward and metal free procedure would serve as a better alternative to the prevalent procedures. Few of the products could also be transformed into heterocyclic scaffolds structurally resembling known bioactive compounds.

4.
J Org Chem ; 81(22): 10987-10999, 2016 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-27779864

RESUMEN

A Pd(II)-catalyzed direct synthesis of benzo[a]carbazoles has been achieved through aminopalladation of alkynes, followed by intramolecular nucleophilic addition of the generated carbon-palladium bond to a tethered cyano/aldehyde group. Compared to literature procedures, this synthetic approach is operationally simple, uses simple substrates, and offers a fast intramolecular assembly resulting in the direct synthesis of benzo[a]carbazoles in which a wide variation of substituents at different sites is well-tolerated, leaving enough opportunity for diversification.

5.
Life Sci ; 351: 122836, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38879159

RESUMEN

AIM: Exploring the efficacy of ß-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics. MATERIALS AND METHODS: We synthesized a series of 1-Aryl-N-substituted-ß-carboline-3-carboxamide compounds and evaluated their cytotoxicity against human lung carcinoma (A549) cells using the MTT assay. Normal lung fibroblast cells (WI-38) were used to assess compound selectivity. The mechanism of action of MJ-211 was elucidated through Western blot analysis of key pro-apoptotic and cell cycle regulatory proteins. Additionally, the inhibitory effect of MJ-211 on multicellular 3D spheroid growth of A549 cells was evaluated. KEY FINDINGS: Lead compound MJ-211 exhibited remarkable cytotoxicity against A549 cells with an IC50 of 4.075 µM at 24 h treatment and IC50 of 1.7 nM after 72 h of treatment, while demonstrating selectivity towards normal WI-38 cells. MJ-211 activated pro-apoptotic factors Bim and p53, and suppressed Cyclin B1, Phospho HSP 27, BubR1, Mad 2, ERK1/2, and NF-κB, indicating its potent antimitotic and pro-apoptotic effects. MJ-211 significantly suppressed the migration of cells and inhibited the growth of A549 cell-derived multicellular 3D spheroids, highlighting its efficacy in a more physiologically relevant model. SIGNIFICANCE: Cytotoxic effect of MJ-211 against cancer cells, selectivity towards normal cells, and ability to modulate key regulatory proteins involved in apoptosis and cell cycle progression underscore its potential as a promising template for further anticancer lead optimization. Moreover, the inhibitory effect of MJ-211 on multicellular spheroid growth suggests its efficacy in combating tumor heterogeneity and resistance mechanisms, thereby offering a promising avenue for future anticancer drug development.


Asunto(s)
Carbolinas , Microtúbulos , FN-kappa B , Humanos , Carbolinas/farmacología , FN-kappa B/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Células A549 , Antimitóticos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos
6.
ACS Infect Dis ; 10(9): 3098-3125, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39137302

RESUMEN

Venom in medicine is well documented in the chronicles of ancient Greece and the Roman Empire and persisted into the Renaissance and even into the modern era. Venoms were not always associated with detrimental consequences. Since ancient times, the curative capacity of venom has been recognized, portraying venom as a metaphor for pharmacy and medicine. Venom proteins and peptides' antimicrobial potential has not undergone systematic exploration despite the huge literature on natural antimicrobials. In light of the escalating challenge of antimicrobial resistance and the diminishing effectiveness of antibiotics, there is a pressing need for innovative antimicrobials capable of effectively addressing illnesses caused by multidrug-resistant microorganisms. This review adds to our understanding of the effectiveness of different venom components against a host of pathogenic microorganisms. The aim is to illuminate the various antimicrobials present in venom and venom peptides, thereby emphasizing the unexplored medicinal potential for antimicrobial properties. We have presented a concise summary of the molecular examination of the venom peptides' functioning processes, as well as the current clinical and preclinical progress of venom antimicrobial peptides.


Asunto(s)
Antiinfecciosos , Ponzoñas , Animales , Humanos , Ponzoñas/química , Ponzoñas/farmacología , Antiinfecciosos/farmacología , Antiinfecciosos/química , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/química
7.
ACS Chem Neurosci ; 15(19): 3482-3495, 2024 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-39288278

RESUMEN

Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain's regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internalized Exo-pep-11 in both in vitro culture conditions as well as in the in vivo aging rats. We found that the uptake of Exo-pep-11 decreased by ∼2.3-fold when NSC was treated with EphA4 antibody before Exo-pep-11 incubation, which confirms the receptor-specific uptake of Exo-pep-11. Exo-pep-11 treatment also increases NSC proliferation by ∼1.9-fold and also shows ∼1.6- and ∼2.4-fold increase in expressions of Nestin and ID1, respectively. Exo-pep-11 also has the potential to increase neurogenesis in aging rats, which is confirmed by ∼1.6- and ∼1.5-fold increases in expressions of TH and Tuj1, respectively, in rat olfactory bulb. Overall, our findings highlight the potential role of Exo-pep-11 for prospective applications in combating age-related declines in NSC activity and neurogenesis.


Asunto(s)
Envejecimiento , Vesículas Extracelulares , Células-Madre Neurales , Neurogénesis , Receptor EphA4 , Animales , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Ratas , Envejecimiento/efectos de los fármacos , Receptor EphA4/metabolismo , Neurogénesis/fisiología , Neurogénesis/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Células Madre Adultas/efectos de los fármacos , Péptidos/farmacología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Rejuvenecimiento/fisiología , Ratas Sprague-Dawley
8.
ACS Appl Bio Mater ; 7(6): 4142-4161, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38770768

RESUMEN

The emergence of antimicrobial resistance, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), poses a grave threat to public health globally. Over time, MRSA has evolved resistance to multiple antibiotics, challenging conventional treatment strategies. The relentless adaptability of MRSA underscores the urgent need for innovative and targeted antimicrobial approaches to combat this resilient pathogen. Ancient knowledge and practices, along with scientific evidence, have established that metallic copper, and its organic coordination complexes can act as potential antibacterial substances. In search of a smart and effective antimicrobial against MRSA, we designed, synthesized, and characterized a bidentate copper(II) ligand complex (SG-Cu) utilizing a comprehensive array of analytical techniques, including ESI-MS, elemental analysis, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, and others. Antibacterial efficacy and mechanism of action of the complex were assessed through bacterial growth analyses, bacterial membrane perturbation assays, ROS elicitation assays, and field emission scanning electron microscopy. SG-Cu was found to maintain robust biocompatibility against the mammalian cell lines HEK-293, WI-38, and NIH/3T3. Remarkably, SG-Cu demonstrated significant biofilm disruptive tendency evidenced by the retardation of sliding motility, reduction in slime production, reduction in biofilm viability, and enhanced biofilm eradication, both in vitro and in urinary catheters. In vivo studies on murine excisional wounds, with SG-Cu impregnated in a palmitic acid conjugated NAVSIQ hexapeptide (PA-NV) hydrogel, revealed the sustained release of SG-Cu from the gel matrix, facilitating accelerated wound healing and effective wound disinfection. This multifaceted investigation highlights the potential of SG-Cu as a versatile option for combating MRSA infections and promoting wound healing, solidifying its claim to be developed into a viable therapeutic.


Asunto(s)
Antibacterianos , Cobre , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina , Compuestos de Organocobre , Quinolinas , Infecciones Estafilocócicas , Cicatrización de Heridas , Infección de Heridas , Quinolinas/síntesis química , Quinolinas/farmacología , Quinolinas/uso terapéutico , Cobre/química , Cobre/farmacología , Cobre/uso terapéutico , Ligandos , Hidrogeles/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Cápsulas , Cicatrización de Heridas/efectos de los fármacos , Humanos , Animales , Ratones , Células HEK293 , Células 3T3 NIH , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismo , Compuestos de Organocobre/síntesis química , Compuestos de Organocobre/farmacología , Compuestos de Organocobre/uso terapéutico
9.
ACS Infect Dis ; 10(4): 1267-1285, 2024 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-38442370

RESUMEN

The escalation of bacterial resistance against existing therapeutic antimicrobials has reached a critical peak, leading to the rapid emergence of multidrug-resistant strains. Stringent pathways in novel drug discovery hinder our progress in this survival race. A promising approach to combat emerging antibiotic resistance involves enhancing conventional ineffective antimicrobials using low-toxicity small molecule adjuvants. Recent research interest lies in weak membrane-perturbing agents with unique cyclic hydrophobic components, addressing a significant gap in antimicrobial drug exploration. Our study demonstrates that quinoline-based amphipathic small molecules, SG-B-52 and SG-B-22, significantly reduce MICs of selected beta-lactam antibiotics (ampicillin and amoxicillin) against lethal methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, membrane perturbation, depolarization, and ROS generation drive cellular lysis and death. These molecules display minimal in vitro and in vivo toxicity, showcased through hemolysis assays, cell cytotoxicity analysis, and studies on albino Wistar rats. SG-B-52 exhibits impressive biofilm-clearing abilities against MRSA biofilms, proposing a strategy to enhance beta-lactam antibiosis and encouraging the development of potent antimicrobial potentiators.


Asunto(s)
Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Quinolinas , beta-Lactamas/farmacología , beta-Lactamas/uso terapéutico , Sinergismo Farmacológico , Antiinfecciosos/farmacología , Quinolinas/farmacología
10.
J Med Chem ; 67(11): 9260-9276, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38771158

RESUMEN

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.


Asunto(s)
Distrofia Muscular de Duchenne , Quinazolinas , Quinolinas , Receptores de Hidrocarburo de Aril , Utrofina , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Utrofina/metabolismo , Quinolinas/farmacología , Quinolinas/química , Humanos , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Animales , Ratones , Quinazolinas/farmacología , Quinazolinas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Relación Estructura-Actividad , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo
11.
J Med Chem ; 66(16): 11555-11572, 2023 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-37566805

RESUMEN

Antimicrobial cationic peptides are intriguing and propitious antibiotics for the future, even against multidrug-resistant superbugs. Venoms serve as a source of cutting-edge therapeutics and innovative, unexplored medicines. In this study, a novel cationic peptide library consisting of seven sequences was designed and synthesized from the snake venom cathelicidin, batroxicidin (BatxC), with the inclusion of the FLPII motif at the N-terminus. SP1V3_1 demonstrated exceptional antibacterial effectiveness against Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae and destroyed the bacteria by depolarizing, rupturing, and permeabilizing their membranes, as evident from fluorescence assays, atomic force microscopy, and scanning electron microscopy. SP1V3_1 was observed to modulate the immune response in LPS-elicited U937 cells and exhibited good antibiofilm activity against MRSA and K. pneumoniae. The peptide promoted wound healing and disinfection in the murine model. The study demonstrated that SP1V3_1 is an exciting peptide lead and may be explored further for the development of better therapeutic peptides.


Asunto(s)
Antiinfecciosos , Desinfectantes , Staphylococcus aureus Resistente a Meticilina , Ratones , Animales , Pruebas de Sensibilidad Microbiana , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Antibacterianos/farmacología , Cicatrización de Heridas , Venenos de Serpiente , Escherichia coli
12.
Chem Commun (Camb) ; 56(100): 15659-15662, 2020 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-33289730

RESUMEN

An atom-economic Pd(ii)-catalysed cascade cyclisation of 2-(biphenylethynyl)anilines tethered to an aldehyde or cyano group leads to the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high yields (up to 95%). The reaction proceeds via amino-palladation of the alkyne followed by nucleophilic addition onto the aldehyde/cyano group. Treatment of 6 with p-TsOH·H2O smoothly provided cyclooctatetraene (COT) derivatives 7.

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