Synthesis of Some Quinoline Oximes by an Efficient Method and their Biological Screening

Quinoline scaffolds have gained substantial interest in the modern era of medicinal chemistry due to their wide range of biological applications. The present work reported the synthesis of various oxime derivatives of quinolines by the reaction of substituted 2-chloro-3-formyl-quinolines with hydroxyl amine hydrochloride. The reaction was mediated by aqueous ethanol, whereas hexamine was used as an efficient, non-toxic and easily available basic organocatalyst. The developed protocol has various advantages, including operational ease, affordability, an eco-friendly approach, and short reaction time. Moreover, the synthesized compounds were subjected to in-vitro antimicrobial activities. The antimicrobial evaluation of almost all the compounds found to be potent and effective. Compounds 4c, 4d, and 4f showed a broad spectrum of inhibition and were more effective when tested against specific Gram (-) and Gram (+) bacteria. In in-vitro antifungal evaluation, all synthesized compounds (4a-4g) showed good sensitivity against the tested fungal cultures except Aspergillus niger.

Experimental study of SPECT imaging with novel myocardial perfusion imaging tracer: 99Tcm-3SPboroxime / 中华核医学与分子影像杂志

Objective To assess the superiority of 99Tcm-3SPboroxime (99Tcm-3SP for short) as a fast-myocardial perfusion imaging (MPI) tracer in normal and acute myocardial infarction (AMI) mini-swine.Methods 99Tcm-3SP and 99Tcm-Teboroxime (99Tcm-TEBO for short) were prepared.Approximately 370 MBq 99Tcm-3SP or 99Tcm-TEBO was injected intravenously in 2 healthy mini-swine separately.Dynamic planar images were acquired immediately after injection and continued for 20 min using a standard SPECT camera.The radioactivity uptakes in the heart,liver,and lungs were measured,and heart/liver and heart/lung ratios over time were calculated.Dynamic SPECT studies were performed in 4 normal swine and 1 AMI-swine using cadmium zinc telluride-SPECT (CZT-SPECT).List mode acquisitions were immediately started and continued for 15 min after intravenous injection of approximately 370 MBq 99Tcm-TEBO and 99Tcm-3SP.The injection of two radiotracers in the same swine was completed within 2 d.The radioactivity uptakes in heart and liver were measured,and heart/liver ratio was calculated.Image quality was also evaluated.Paired t test was used to analyze the data.Results The radiochemical purity of 99Tcm-TEBO or 99Tcm-3SP were both above 95％.The initial heart uptake of 99Tcm-3SP was very close to that of 99Tcm-TEBO (planar image,2 min postinjection:309.32× 103 vs 314.13 × 103 counts/MBq;SPECT image,2 min postinjection (corrected):7.96±0.87 vs 8.24± 1.53,t =0.277,P＞0.05),but the myocardial retention time was much longer than that of 99Tcm-TEBO (planar image,20 min postinjection:218.67× 103 vs 143.19× 103 counts/MBq;SPECT image,15 min postinjection (corrected):6.76±0.45 vs 5.06±0.33,t =-12.412,P =0.001).The uptake of liver and heart/liver ratio between 99Tcm-TEBO and 99Tcm-3SP were similar (t values:-1.332-1.101,all P＞0.05 within 15 min).SPECT MPI images demonstrated uniform tracer distribution with clearly visualizable myocardial boundary in normal myocardium and intense perfusion defect in infarct myocardium.High quality SPECT images could be obtained in any of the 5 min imaging windows over the first 15 min after injection of 99Tcm-3SP in normal swine and AMI-swine.Conclusion 99Tcm-3SP is a promising 99 Tcm-labeled radiotracer for fast-MPI considering its high heart uptake,long myocardial retention time (20 min postinjection) and superior SPECT image quality.

Experimental study of SPECT imaging with novel myocardial perfusion imaging tracer: 99Tcm-3SPboroxime / 中华核医学与分子影像杂志

Objective@#To assess the superiority of 99Tcm-3SPboroxime (99Tcm-3SP for short) as a fast-myocardial perfusion imaging (MPI) tracer in normal and acute myocardial infarction (AMI) mini-swine.@*Methods@#99Tcm-3SP and 99Tcm-Teboroxime (99Tcm-TEBO for short) were prepared. Approximately 370 MBq 99Tcm-3SP or 99Tcm-TEBO was injected intravenously in 2 healthy mini-swine separately. Dynamic planar images were acquired immediately after injection and continued for 20 min using a standard SPECT camera. The radioactivity uptakes in the heart, liver, and lungs were measured, and heart/liver and heart/lung ratios over time were calculated. Dynamic SPECT studies were performed in 4 normal swine and 1 AMI-swine using cadmium zinc telluride-SPECT (CZT-SPECT). List mode acquisitions were immediately started and continued for 15 min after intravenous injection of approximately 370 MBq 99Tcm-TEBO and 99Tcm-3SP. The injection of two radiotracers in the same swine was completed within 2 d. The radioactivity uptakes in heart and liver were measured, and heart/liver ratio was calculated. Image quality was also evaluated. Paired t test was used to analyze the data.@*Results@#The radiochemical purity of 99Tcm-TEBO or 99Tcm-3SP were both above 95%. The initial heart uptake of 99Tcm-3SP was very close to that of 99Tcm-TEBO (planar image, 2 min postinjection: 309.32×103 vs 314.13×103 counts/MBq; SPECT image, 2 min postinjection (corrected): 7.96±0.87 vs 8.24±1.53, t=0.277, P>0.05), but the myocardial retention time was much longer than that of 99Tcm-TEBO (planar image, 20 min postinjection: 218.67×103 vs 143.19×103 counts/MBq; SPECT image, 15 min postinjection (corrected): 6.76±0.45 vs 5.06±0.33, t=-12.412, P=0.001). The uptake of liver and heart/liver ratio between 99Tcm-TEBO and 99Tcm-3SP were similar (t values: -1.332-1.101, all P>0.05 within 15 min). SPECT MPI images demonstrated uniform tracer distribution with clearly visualizable myocardial boundary in normal myocardium and intense perfusion defect in infarct myocardium. High quality SPECT images could be obtained in any of the 5 min imaging windows over the first 15 min after injection of 99Tcm-3SP in normal swine and AMI-swine.@*Conclusion@#99Tcm-3SP is a promising 99Tcm-labeled radiotracer for fast-MPI considering its high heart uptake, long myocardial retention time (20 min postinjection) and superior SPECT image quality.

Enzimas degradantes de organofosforados: Base molecular e perspectivas para biorremediação enzimática de agroquímicos / Organophosphorus degrading enzymes: Molecular basis and perspectives for enzymatic bioremediation of agrochemicals

RESUMO Muitos compostos organofosforados (OP) são utilizados até hoje na agricultura como pesticidas e, infelizmente, como agentes de guerra química (ou agentes dos nervos) também. Os pesticidas organofosforados e os agentes dos nervos são moléculas extremamente tóxicas, uma vez que atuam como inibidores da enzima Acetilcolinesterase (AChE). O efeito mais preocupante da exposição a estes compostos é a toxicidade colinérgica aguda, ou seja, a perda de coordenação muscular. Uma vez que o indivíduo se contamina, o processo de intoxicação começa através da ligação do OP no sítio ativo da enzima AChE inativando-a. Os tratamentos atuais para pessoas expostas a baixas doses de OP podem ser realizados com atropina, oximas e benzodiazepínicos. Processos de remediação importantes envolvem o emprego de técnicas de biorremediação utilizando diferentes enzimas degradantes, como a Fosfotriesterase da Agrobacterium radiobacter e SMP-30. Devido ao elevado número de intoxicações anualmente, é crucial buscar métodos de tratamento mais potentes e eficazes, e nesta linha, as técnicas envolvendo biorremediação parecem ser bastante promissoras para este propósito.

ABSTRACT Many organophosphorus compounds (OP) are used until today in agriculture as pesticides and, unfortunately, they are used as chemical warfare agents (or nerve agents) as well. Organophosphorus pesticides and nerve agents are extremely toxic molecules, since they act as Acetylcholinesterase (AChE) inhibitors. The most worrying effect of the exposure to these compounds is the acute cholinergic toxicity, which is the loss of muscle coordination. Once one is contaminated, the intoxication process begins through the binding of the OP in the active site of the AChE enzyme inactivating it. Current treatments for people exposed to low doses of OP can be performed with atropine, oximes and benzodiazepines. Important remediation processes involve the employment of bioremediation techniques using different degrading enzymes, such as the Phosphotriesterase from Agrobacterium radiobacter and SMP-30. Due to the high number of intoxications annually, it is crucial to search for more potent and effective treatment methods, and in this line, the techniques involving bioremediation seem to be quite promising for this purpose.

Drug research and clinical application of organophosphorous poisoning / 中国药理学与毒理学杂志

Acute organophosphorus pesticides poisoning(AOPP)is one of the common critical emergency problems and the fatality is extremely high. Organophosphorus pesticides(OPS)are highly effective acetylcholinesterase(AChE)inhibitors. The AChE inhibition results in accumulation of acetyl?choline and overestimation of acetylcholine receptors in synapses of the autonomic nervous system, central nervous system,and neuromuscular junctions,causing a series of symptoms including musca?rinic,nicotinic,and central nervous system dysfunctions. In the early stage of AOPP,the core treat?ment is the use of anticholinergic drugs coupled with cholinesterase reactivator. Atropine and penehycli?dine hydrochloride(Tuoning)are the most commonly used anticholinergic drugs,which can effectively compete with acetylcholine receptors,block the effect of acetylcholine,and relieve the symptoms of re?spiratory failure,bronchospasm,pulmonary edema caused by AOPP. Oximes are believed to function as AChE reactivators,that can promote enzymatic reactivation and restore the activity of hydrolysis of ace? tylcholine. Recently,new avproaches,such as intravenous lipid emulsion,new detoxification drugs, blood purification,and traditional Chinese medicine,have attracted more attention. Overall,great prog?ress has been made in AOPP treatments. A better understanding of AOPP mechanism,and the support from pharmacology,toxicology,and related fields can contribute to the treatment of AOPP. Improved medical management of AOPP can also result in fewer deaths from poisoning worldwide.

Síntesis y evaluación in vitro de la actividad antifúngica de oximas, éteres de oxima e isoxazoles / Síntese e avaliação in vitro da atividade antifúngica de oximas, éteres de oxima e isoxazóis / Synthesis and in vitro assessment of antifungal activity of oximes, oxime ethers and isoxazoles

Objetivo. Sintetizar y realizar la evaluación preliminar de la actividad antifúngica in vitro de oximas, éteres de oxima e isoxazoles. Materiales y métodos. Las oximas se sintetizaron a partir de aldehídos o cetonas con NH2OH.HCl y K2CO3. Los éteres de oxima se obtuvieron mediante alquilación de oximas con bromuro de propargilo o bromuro de 2-bromobencilo, empleando como base NaOH y acetona como solvente. Los isoxazoles se obtuvieron mediante cicloadiciones 1,3-dipolares empleando nitrato cérico amónico (NAC), cloramina-T (CAT) y NaOCl. Los productos fueron identificados y/o caracterizados por resonancia magnética nuclear (RMN) y espectrometría de masas (EM). Se realizaron pruebas de inhibición de crecimiento radial sobre Aspergillus niger y Fusarium roseum. Resultados. Se obtuvieron cinco oximas, siete éteres de oxima, cuatro de ellos nuevos y cuatro nuevos isoxazoles. Las sustancias evaluadas presentaron actividad antifúngica a cantidades de 1,5 mg y 3,0 mg. Conclusiones. Aunque las cicloadiciones 1,3-dipolares permitieron obtener los isoxazoles esperados, se observó que ésta metodología generó una amplia variedad de subproductos lo que disminuyó los rendimientos e hizo difícil la purificación del producto de interés. Cuatro de las sustancias evaluadas presentaron porcentajes de inhibición superiores al 80%...

Synthesis and in vitro assessment of antifungal activity of oximes, oxime ethers and isoxazoles. Objective. To synthesize and carry out a preliminary evaluation of the in vitro antifungal activity of oximes, oxime ethers and isoxazoles. Materials and methods. Oximes were synthesized from aldehydes or ketones with NH2OH.HCl and K2CO3. Oxime ethers were prepared by alkylation of oximes with propargyl bromide or 2-bromobenzyl bromide, using NaOH as base and acetone as solvent. The isoxazoles were obtained by 1,3-dipolar cycloadditions using ceric ammonium nitrate (CAN), chloramine T (CAT) and NaOCl. Products were identified or characterized using nuclear magnetic resonance (NMR) and mass spectrometry (MS). Radial growth inhibition assays against Aspergillus niger and Fusarium roseum were carried out. Results. Five oximes, seven oxime ethers, four of them new, and four new isoxazoles were obtained. The assessed substances exhibited antifungal activity in amounts of 1,5 mg and 3,0 mg. Conclusions. Although 1,3-dipolar cycloadditions allowed to obtain the desired isoxazoles, this methodology produced a wide variety of side products that reduced yields and made difficult the purification of the target products. Four of the tested compounds showed inhibition percentages greater than 80%...

Síntese e avaliação “in vitro” da atividade antifúngica de oximas, éteres de oxima e isoxazóis. Objetivo. Sintetizar e realizar a avaliação preliminar da atividade antifúngica in vitro de oximas, éteres de oxima e isoxazóis. Materiais e métodos. As oximas foram sintetizadas a partir de aldeídos ou cetonas com NH2OH.HCl e K2CO3. Os éteres de oxima foram obtidos pela alquilação de oximas com brometo de propargilo ou brometo de 2-bromobenzilo, utilizando NaOH como base e acetona como solvente. Os isoxazóis foram obtidos por cicloadição 1,3-dipolar usando nitrato cérico de amônio (NCA), cloramina-T (CAT) e NaOCl. Os produtos foram identificados e / ou caracterizados por ressonância magnética nuclear (RMN) e espectrometria de massas (EM). Foram realizados testes de inibição sobre o crescimento radial de Aspergillus niger e Fusarium roseum. Resultados. Foram obtidas cinco oximas, sete éteres de oxima, quatro deles novos e quatro novos isoxazóis. As substâncias testadas apresentaram atividade antifúngica em quantidades de 1,5 mg e 3,0 mg. Conclusões. Embora as cicloadições 1,3-dipolares permitiram obter os isoxazóis esperados, observou-se que esta metodologia resultou numa grande variedade de subprodutos que reduziram os rendimentos e tornaram difícil a purificação do produto de interesse. Quatro das substâncias testadas apresentaram porcentagens de inibição acima de 80%...

Intoxicación por organofosforados con necesidad de altas dosis de atropina y administración tardía de oximas / Organophosphate poisoningin need of high dose of atropine and late administration of Oxime

La intoxicación por organofosforados es una de las causas más frecuentes de intoxicación en el mundo y una de las tres formas principales de suicidio, llegando a mortalidades cercanas al 15%. Esta radica en la inhibición irreversible que sus componentes hacen en la enzima acetilcolinesterasa, llevando con ello a la aparición de signos y síntomas secundarios al exceso de acetilcolina en los sistemas donde actúa. Su manejo aún es controvertido y sigue basándose en las medidas de descontaminación, utilización de atropina, oximas y benzodiacepinas, sin haber consenso en muchas de las dosis e intervalos de tiempo para la administración de estos medicamentos. En este artículo exponemos un caso en el cual se hace necesario utilizar dosis e intervalos de administración de atropina y el uso tardío de las oximas. Con este caso se puede concluir que la administración tardía de oximas y la utilización de grandes cantidades de atropina pueden ser una alternativa en el manejo de este tipo de intoxicación. [Leotau MA, Pacheco SH, Tavera CH. Intoxicación por organofosforados con necesidad de altas dosis de atropina y administración tardía de oximas. MedUNAB 2010; 13:44-50].

Organophosphate poisoning is one of the most frequent causes of poisoning in the world and one of the three main forms of suicide, reaching roughly 15% mortality, this lies in the irreversible inhibition that make components in the enzyme acetylcholinesterase, leading thus the signs and symptoms secondary to excessive acetylcholine in the systems where it operates. Its management is still controversial and remains based on the decontamination measures, use of atropine, oximes and benzodiazepines, no consensus on many of the doses and time intervals for administration of these drugs. In this article we present a case in which it becomes necessary to use dose and timing of administration of atropine and late use of oximes. In this case we can conclude that the late administration of oximes using grades and quantities of atropine may be an alternative in handling this type of poisoning. [Leotau MA, Pacheco SH, Tavera CH. Organophosphate poisoning treated with high doses of atropine and late administration of oxime. MedUNAB 2010; 13:44-50].