The antibacterial effects of new N-alkylpyridinium salts on planktonic and biofilm bacteria

An increasing microbial resistance to known antibiotics raises a demand for new antimicrobials. In this study the antimicrobial properties of a series of new N-Alkylpyridinium quaternary ammonium compounds (QACs) with varying alkyl chain lengths were evaluated for several nosocomial pathogens. The chemical identities of the new QACs were determined by NMR, LC-MS, and HRMS. All the planktonic bacteria tested were susceptible to the new QACs as evaluated by MIC and MBC assays. The antimicrobial effect was most pronounced against Staphylococcus aureus clinical isolates. Live/dead staining CLSM was used to test the effectiveness of the QACs in biofilms. The effectiveness was up to 10-fold lower than in the plankton. When QACs were used as irrigants in Er:YAG – SSP photoacoustic steaming, their effectiveness significantly increased. The combined use of irrigants and photoacoustic streaming increased biofilm removal from the surface and increased the killing rate of the cells remaining on the surface. This may allow for a shorter chemical exposure time and lower dosage of QACs used in applications. The results demonstrate that the new QACs have potential to be applied as antibacterial compounds effective against planktonic and biofilm bacteria as well as irrigants in removal of difficult-to-reach biofilms

Synthesis and Decontamination Effect on Chemical and Biological Agents of Benzoxonium-Like Salts

Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C10-C18 set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents

Synthesis and In Vitro Evaluation of Novel Dopamine Receptor D2 3,4-dihydroquinolin-2(1H)-one Derivatives Related to Aripiprazole

In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure–activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood–brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301

Structure-guided design of N-methylpropargylamino-quinazoline derivatives as multipotent agents for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.Alzheimerova choroba (AD) je komplexní onemocnění s neznámou etiologií. Dostupná léčba, omezená na inhibitory cholinesterázy a antagonisty N-methyl-d-aspartátového receptoru (NMDAR), poskytuje pouze symptomatickou úlevu. Jelikož se "jednocílová" terapie neprokázala jako účinná, představuje kombinovaná specificky cílená terapie do jediné molekuly slibnější přístup k léčbě AD a očekává se, že přinese větší přínos při zmírňování symptomů a zpomalení progrese onemocnění. V této studii jsme navrhli, syntetizovali a biologicky vyhodnotili 24 nových N-methylpropargylamino-chinazolinových derivátů. Zpočátku byly sloučeniny důkladně kontrolovány technikami in silico, které určovaly jejich orální a CNS dostupnost. Testovali jsme in vitro účinky sloučenin na cholinesterázy a monoaminooxidázu A/B (MAO-A/B), stejně jako jejich dopad na antagonismus NMDAR, aktivitu dehydrogenázy a hladiny glutathionu. Kromě toho jsme zkoumali vybrané sloučeniny na jejich cytotoxicitu na nediferencovaných a diferencovaných buňkách neuroblastomu SH-SY5Y. Společně jsme vyzdvihli II-6h jako nejlepšího kandidáta s profilem selektivní inhibice MAO-B, antagonismem NMDAR, přijatelným profilem cytotoxicity a potenciálem pronikat přes BBB. Strategie navrhování léků řízená strukturou použitá v této studii vnutila nový koncept racionálního objevování léků a zlepšuje naše chápání vývoje nových terapeutických látek pro léčbu AD