Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina
Autor(a) principal: | |
---|---|
Data de Publicação: | 2022 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/26263 |
Resumo: | Pseudomonas aeruginosa is an opportunistic bacterium that rarely causes infection in healthy people. However, it is among the main agents in nosocomial infections, with high rates of morbidity and mortality due to its multidrug resistance (MDR). This microorganism is capable of triggering serious infections in immunocompromised individuals, the most susceptible being those hospitalized in intensive care units, burn patients and cystic fibrosis patients.Although there are many classes of antibiotics available for treatment, infections by multidrug-resistant strains are increasingly common, especially in the hospital environment. These sites, in addition to the circulation of susceptible and immunocompromised individuals, present favorable conditions for the transmission and selective pressure of the strains, favoring the emergence of multidrug-resistant isolates. Carbapenem-resistant P. aeruginosa were included in the World Health Organization (WHO) list of three species of bacteria in critical need for the development of new antibiotics. Heterocyclic compounds derived from pyrazolines have been synthesized and used in studies due to their characteristics and various pharmacological properties. Computational tools (in silico) have been proposed in order to reduce the time and high costs involved in this process. These technologies allow the association of computational predictions with pre-clinical laboratory tests (in vitro and in vivo), making these models cost-effective in drug research and development. In view of the urgent need to discover new antibiotics or therapeutic alternatives for the treatment of multidrug-resistant infections caused by this pathogen, the present study aimed to evaluate the antibacterial activity of seven new compounds derived from pyrazolines in multidrug-resistant clinical isolates of P. aeruginosa and to study their properties. physicochemical, pharmacokinetic and toxicological properties using in silico tools. To evaluate the antibacterial activity of the drugs, the determination of the minimum inhibitory concentration (MIC) was performed. The cytotoxicity of the compounds was evaluated in assays with the fibroblast cell line (VERO). The pyrazoline compounds that showed activity had a MIC of 0.2 mg/mL compared to clinical isolates and IC50 values that ranged from 0.0081mg/mL to 0.4577mg/mL. Regarding the pharmacokinetic and toxicological results (in silico), the analyzed compounds did not violate the rule of five, established by Lipinski. In addition to these parameters, the number of rotational bonds was less than 10 (between 3 and 4) and the TPSA was less than 140 Å (65.79), which confirmed a good oral bioavailability of the analyzed compounds. The in silico prediction and their respective antimicrobial activities of the molecules analyzed here, with reservations and possible molecular rearrangements, allows us to suggest them as potential candidates for drugs to be used orally with good permeability through biological membranes and high absorption by the gastrointestinal route. |
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2022-09-26T19:52:00Z2022-09-26T19:52:00Z2022-08-24http://repositorio.ufsm.br/handle/1/26263Pseudomonas aeruginosa is an opportunistic bacterium that rarely causes infection in healthy people. However, it is among the main agents in nosocomial infections, with high rates of morbidity and mortality due to its multidrug resistance (MDR). This microorganism is capable of triggering serious infections in immunocompromised individuals, the most susceptible being those hospitalized in intensive care units, burn patients and cystic fibrosis patients.Although there are many classes of antibiotics available for treatment, infections by multidrug-resistant strains are increasingly common, especially in the hospital environment. These sites, in addition to the circulation of susceptible and immunocompromised individuals, present favorable conditions for the transmission and selective pressure of the strains, favoring the emergence of multidrug-resistant isolates. Carbapenem-resistant P. aeruginosa were included in the World Health Organization (WHO) list of three species of bacteria in critical need for the development of new antibiotics. Heterocyclic compounds derived from pyrazolines have been synthesized and used in studies due to their characteristics and various pharmacological properties. Computational tools (in silico) have been proposed in order to reduce the time and high costs involved in this process. These technologies allow the association of computational predictions with pre-clinical laboratory tests (in vitro and in vivo), making these models cost-effective in drug research and development. In view of the urgent need to discover new antibiotics or therapeutic alternatives for the treatment of multidrug-resistant infections caused by this pathogen, the present study aimed to evaluate the antibacterial activity of seven new compounds derived from pyrazolines in multidrug-resistant clinical isolates of P. aeruginosa and to study their properties. physicochemical, pharmacokinetic and toxicological properties using in silico tools. To evaluate the antibacterial activity of the drugs, the determination of the minimum inhibitory concentration (MIC) was performed. The cytotoxicity of the compounds was evaluated in assays with the fibroblast cell line (VERO). The pyrazoline compounds that showed activity had a MIC of 0.2 mg/mL compared to clinical isolates and IC50 values that ranged from 0.0081mg/mL to 0.4577mg/mL. Regarding the pharmacokinetic and toxicological results (in silico), the analyzed compounds did not violate the rule of five, established by Lipinski. In addition to these parameters, the number of rotational bonds was less than 10 (between 3 and 4) and the TPSA was less than 140 Å (65.79), which confirmed a good oral bioavailability of the analyzed compounds. The in silico prediction and their respective antimicrobial activities of the molecules analyzed here, with reservations and possible molecular rearrangements, allows us to suggest them as potential candidates for drugs to be used orally with good permeability through biological membranes and high absorption by the gastrointestinal route.Pseudomonas aeruginosa é uma bactéria oportunista que raramente causa infecção em pessoas sadias. Porém figura entre os principais agentes em infecções nosocomiais, com altas taxas de morbidade e mortalidade devido a sua resistência a múltiplos fármacos (MDR). Este microorganismo é capaz de desencadear infecções graves em indivíduos imunocomprometidos, sendo os mais susceptíveis aqueles internados em unidades de terapia intensiva, pacientes queimados e com fibrose cística. Apesar de existirem muitas classes de antibióticos disponíveis para o tratamento é cada vez mais comum a ocorrência de infecções por cepas multirresistentes, principalmente no ambiente hospitalar. Esses locais, além da circulação de indivíduos susceptíveis e imunocomprometidos, apresentam condições favoráveis para transmissão e pressão seletiva das cepas, favorecendo o surgimento de isolados multirresistentes. P. aeruginosa resistente aos carbapenêmicos foram incluídas na lista da Organização Mundial de Saúde (OMS) entre as três espécies de bactérias com necessidade crítica para o desenvolvimento de novos antibióticos. Compostos heterocíclicos derivados de pirazolinas vêm sendo sintetizados e utilizados em estudos pelas suas características e diversas propriedades farmacológicas. Ferramentas computacionais (in silico) têm sido propostas a fim de reduzir o tempo e altos custos envolvidos neste processo. Estas tecnologias permitem associar predições computacionais aos ensaios pré-clínicos laboratoriais (in vitro e in vivo), tornando estes modelos custo-efetivos na pesquisa e desenvolvimento de fármacos. Tendo em vista, a urgente necessidade em descobrir novos antibióticos ou alternativas terapêuticas para o tratamento de infecções multirresistentes por este patógeno o presente estudo teve como objetivo avaliar a atividade antibacteriana de sete novos compostos derivados de pirazolinas em isolados clínicos multirresistentes de P. aeruginosa e estudar suas propriedades físico-químicas, farmacocinéticas e toxicológicas utilizando ferramentas in silico. Para avaliar a atividade antibacteriana dos fármacos foi realizado a determinação da concentração inibitória mínima (CIM). A citotoxicidade dos compostos foi avaliada em ensaios com a linhagem celular de fibroblasto (VERO). Os compostos pirazolínicos que apresentaram atividade tiveram uma CIM de 0,2 mg/mL frente aos isolados clínicos e valores de IC50 que variou em 0,0081mg/mL e 0,4577mg/mL. Em relação aos resultados farmacocinéticos e toxicológicos (in silico) os compostos analisados não violaram a regra dos cinco, instituída por Lipinski. Além desses parâmetros, o número de ligações rotacionais esteve menor que 10 (entre 3 e 4) e a TPSA esteve menor que 140 Å (65,79), o que ratificou uma boa biodisponibilidade oral dos compostos analisados. A previsão in silico e suas respectivas atividades antimicrobianas das moléculas aqui analisadas, com ressalvas e possíveis rearranjos moleculares nos permite sugeri-las como potenciais candidatos a fármacos a serem utilizados pela via oral com boa permeabilidade através de membranas biológicas e alta absorção por via gastrintestinal.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilAnálises Clínicas e ToxicológicasAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessPseudomonas aeruginosaAtividade antibacterianaIn silicoPirazolinaAntibacterial activityPyrazolineCNPQ::CIENCIAS DA SAUDE::FARMACIAEstudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolinaStudy of antibacterial, physicochemical, pharmacokinetic and toxicological activity of new pyrazoline-derived compoundsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisHorner, Rosmarihttp://lattes.cnpq.br/5907084134183708Ramos, Daniela FernandesSantos, Aline Joana Rolina Wohlmuth Alves dosRamos, Daniela Fernandeshttp://lattes.cnpq.br/8758263609363945Mota, Augusto Dias da4003000000056006006006006006005fdaffc5-abc5-4607-8952-fc5c4760b004524f2f0a-1754-4344-beb4-c5ccc4535856dfa9c75f-44bc-4b7f-b38c-ae35f337654fce578765-c3ea-444f-a5c5-1bbe76c91650f0dff189-4c67-4e69-a9a5-0df0b78a69b9reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGCF_2022_MOTA_AUGUSTO.pdfDIS_PPGCF_2022_MOTA_AUGUSTO.pdfDissertação de mestradoapplication/pdf711175http://repositorio.ufsm.br/bitstream/1/26263/1/DIS_PPGCF_2022_MOTA_AUGUSTO.pdf18ba3cf92e41b5765bda56c6af19b57aMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
dc.title.alternative.eng.fl_str_mv |
Study of antibacterial, physicochemical, pharmacokinetic and toxicological activity of new pyrazoline-derived compounds |
title |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
spellingShingle |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina Mota, Augusto Dias da Pseudomonas aeruginosa Atividade antibacteriana In silico Pirazolina Antibacterial activity Pyrazoline CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
title_full |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
title_fullStr |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
title_full_unstemmed |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
title_sort |
Estudo da atividade antibacteriana, físico químicas farmacocinéticas e toxicológicas de novos compostos derivados de pirazolina |
author |
Mota, Augusto Dias da |
author_facet |
Mota, Augusto Dias da |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Horner, Rosmari |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5907084134183708 |
dc.contributor.advisor-co1.fl_str_mv |
Ramos, Daniela Fernandes |
dc.contributor.referee1.fl_str_mv |
Santos, Aline Joana Rolina Wohlmuth Alves dos |
dc.contributor.referee2.fl_str_mv |
Ramos, Daniela Fernandes |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/8758263609363945 |
dc.contributor.author.fl_str_mv |
Mota, Augusto Dias da |
contributor_str_mv |
Horner, Rosmari Ramos, Daniela Fernandes Santos, Aline Joana Rolina Wohlmuth Alves dos Ramos, Daniela Fernandes |
dc.subject.por.fl_str_mv |
Pseudomonas aeruginosa Atividade antibacteriana In silico Pirazolina |
topic |
Pseudomonas aeruginosa Atividade antibacteriana In silico Pirazolina Antibacterial activity Pyrazoline CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Antibacterial activity Pyrazoline |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Pseudomonas aeruginosa is an opportunistic bacterium that rarely causes infection in healthy people. However, it is among the main agents in nosocomial infections, with high rates of morbidity and mortality due to its multidrug resistance (MDR). This microorganism is capable of triggering serious infections in immunocompromised individuals, the most susceptible being those hospitalized in intensive care units, burn patients and cystic fibrosis patients.Although there are many classes of antibiotics available for treatment, infections by multidrug-resistant strains are increasingly common, especially in the hospital environment. These sites, in addition to the circulation of susceptible and immunocompromised individuals, present favorable conditions for the transmission and selective pressure of the strains, favoring the emergence of multidrug-resistant isolates. Carbapenem-resistant P. aeruginosa were included in the World Health Organization (WHO) list of three species of bacteria in critical need for the development of new antibiotics. Heterocyclic compounds derived from pyrazolines have been synthesized and used in studies due to their characteristics and various pharmacological properties. Computational tools (in silico) have been proposed in order to reduce the time and high costs involved in this process. These technologies allow the association of computational predictions with pre-clinical laboratory tests (in vitro and in vivo), making these models cost-effective in drug research and development. In view of the urgent need to discover new antibiotics or therapeutic alternatives for the treatment of multidrug-resistant infections caused by this pathogen, the present study aimed to evaluate the antibacterial activity of seven new compounds derived from pyrazolines in multidrug-resistant clinical isolates of P. aeruginosa and to study their properties. physicochemical, pharmacokinetic and toxicological properties using in silico tools. To evaluate the antibacterial activity of the drugs, the determination of the minimum inhibitory concentration (MIC) was performed. The cytotoxicity of the compounds was evaluated in assays with the fibroblast cell line (VERO). The pyrazoline compounds that showed activity had a MIC of 0.2 mg/mL compared to clinical isolates and IC50 values that ranged from 0.0081mg/mL to 0.4577mg/mL. Regarding the pharmacokinetic and toxicological results (in silico), the analyzed compounds did not violate the rule of five, established by Lipinski. In addition to these parameters, the number of rotational bonds was less than 10 (between 3 and 4) and the TPSA was less than 140 Å (65.79), which confirmed a good oral bioavailability of the analyzed compounds. The in silico prediction and their respective antimicrobial activities of the molecules analyzed here, with reservations and possible molecular rearrangements, allows us to suggest them as potential candidates for drugs to be used orally with good permeability through biological membranes and high absorption by the gastrointestinal route. |
publishDate |
2022 |
dc.date.accessioned.fl_str_mv |
2022-09-26T19:52:00Z |
dc.date.available.fl_str_mv |
2022-09-26T19:52:00Z |
dc.date.issued.fl_str_mv |
2022-08-24 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
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http://repositorio.ufsm.br/handle/1/26263 |
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http://repositorio.ufsm.br/handle/1/26263 |
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por |
language |
por |
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400300000005 |
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600 600 600 600 600 600 |
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Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Farmacêuticas |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Análises Clínicas e Toxicológicas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
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