RESUMEN

Biofilms facilitate the pathogenesis of life-threatening Pseudomonas aeruginosa infections by coating mucosal surfaces or invasive devices and offer protection from antimicrobial therapy and the host immune response, thus increasing mortality rates and financial burden. Herein, new hybrid N-acylcysteines (NAC) incorporating selected acyl groups from organic acids and their derivatives, which are capable of quenching pathogen quorum sensing (QS) systems, were designed and their antibiofilm activity and anti-QS were evaluated. N-acylcysteines (4a-h) were synthesized and characterized by 1H NMR and 13C NMR, and their purity was confirmed by elemental analyses. N-(4-Hydroxy-3,5-dimethoxybenzoyl)-l-cysteine (4d) and N-(4-methoxybenzoyl)-l-cysteine (4h) showed a higher antibiofilm activity against PAO1 biofilms than the rest of the targets and the standard NAC. They showed 83 and 82% inhibition of biofilms at 5 mM and eradicated mature biofilms at 20 mM concentrations (NAC biofilm inhibition = 66% at 10 mM and minimum biofilm eradication concentration = 40 mM). This was confirmed via visualizing adherent biofilm cells on catheter pieces using scanning electron microscopy. In the same vein, both 4d and 4h showed the highest docking score with the QS signal receptor protein LasR (-7.8), which was much higher than that of NAC (-5) but less than the score of the natural agonist N-(3-oxododecanoyl)-l-homoserine (OdDHL) (-8.5). Target 4h (5 mM) decreased the expression of quorum sensing encoding genes in P. aeruginosa PAO1 strain by 53% for pslA, 47% for lasI and lasR, and 29% for filC, lowered PAO1 pyocyanin production by 76.43%, completely blocked the proteolytic activity of PAO1, and did not affect PAO1 cell viability. Targets 4d and 4h may find applications for the prevention and treatment of biofilm-mediated P. aeruginosa local infections of the skin, eye, and wounds. N-(4-Methoxybenzoyl)-l-cysteine 4h is a promising dual-acting matrix disruptive and anti-QS antibiofilm agent for further investigation and optimization.

RESUMEN

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

Asunto(s)

Inhibidores de la Colinesterasa , Nootrópicos , Acetilcolinesterasa/metabolismo , Animales , Carbamatos/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Donepezilo , Piperazinas , Ratas , Receptores de N-Metil-D-Aspartato

RESUMEN

Cisplatin (CP) is an effective chemotherapeutic agent for treatment of various types of cancer, however efforts are needed to reduce its toxic side effect. Previous studies revealed promising effect of peptides in decreasing CP induced nephrotoxicity. Herein, novel Met-based peptidomimetics were synthesized using N-acylbenzotriazole as acylating agent in high yield. Evaluation of renoprotective effect of the synthesized targets on CP treated kidney cell line (LLC-PK1) revealed that pretreatment with 1/3 IC50 of targets II, IIIa-g attenuated CP induced cell death where the IC50 of CP was raised from 3.28 µM to 9.25-41.1 µM. The most potent compounds IIIg, II and IIIb exhibited antioxidative stress in CP-treated LLC-PK1 cells as confirmed by raising GSH/GSSG ratio and SOD concentration as well as decreasing ROS and MDA. Additionally, in vivo experiments using Sprague Dawley rats showed renoprotective effect of IIIg against CP-induced nephrotoxicity as evidenced by improved results of renal function tests and attenuated CP-induced renal structural injury. Moreover, antioxidant activity of IIIg was demonstrated via its ability to reduce renal MDA level and up-regulate renal antioxidant element GSH level. Further, immunohistochemistry of renal specimens showed the ability of IIIg to restore CP-induced suppression of Nrf2. Interestingly, in vivo and in vitro studies demonstrated that IIIg had no effect on CP antiproliferative activity. An assessment of the ADMET properties revealed that targets IIIg, II and IIIb showed good drug-likeness in terms of their physicochemical, pharmacokinetic properties. The findings presented here showcase that IIIg is a promising renoprotective candidate with antioxidative stress potential.

Asunto(s)

Diseño de Fármacos , Metionina/farmacología , Peptidomiméticos/farmacología , Sustancias Protectoras/farmacología , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular , Cisplatino/antagonistas & inhibidores , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Metionina/síntesis química , Metionina/química , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Sustancias Protectoras/síntesis química , Sustancias Protectoras/química , Relación Estructura-Actividad

RESUMEN

Cephalexin (1) was acylated using N-acylbenzotriazoles (3a-k') derived from various carboxylic acids including aromatic, heterocyclic and N-Pg-α-amino acid to afford N-acylcephalexins in excellent yields (82%-96%). Antibacterial screening of the novel cephalosporins revealed that all targets (4a-j) retained the antibacterial activity of cephalexin against Staphylococcus aureus (ATCC 6538). N-Nicotinylcephalexin (4c) and N-(3,4,5-trimethoxybenzoyl)cephalexin (4g) exhibited a broader spectrum of antibacterial activity towards standard strains of Staphylococcus aureus (ATCC 6538), Paenibacillus polymyxa (ATCC 842), and Escherichia coli (ATCC 10536) as well as a resistant strain of Pseudomonas aeruginosa (ATCC 27853).