Programa de Pós-Graduação em Química Medicinal e Modelagem Molecular - PPGQMMM/ICS

URI Permanente desta comunidadehttps://repositorio.ufpa.br/handle/2011/14430

Navegar

Agora exibindo 1 - 7 de 7

Acesso aberto (Open Access)
Planejamento e desenvolvimento de análogos da nitazoxanida
(Universidade Federal do Pará, 2018-09-25) FERREIRA, Lanalice Rodrigues; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Nitazoxanide is a molecule applied in the antihelminthic therapy and has a broad spectrum as antiparasitic agent. In biological studies by using this molecule, new therapeutic targets and good results were found. Nevertheless, it still has some chemical and pharmaceuticals problems which need improvements. The objective of the study is the design and development of stable nitazoxanide derivatives using molecular modeling and organic synthesis approaches. All calculations of electronic properties such as frontier orbital (HOMO and LUMO), ionization potential (IP) and electronic affinity (AE), electrostatic potential map (MPE) were performed using the Gaussview e Gaussian. The theoretical study of nine amino-nitro-azolic derivatives, an essential moiety of nitazoxanide pharmacophore, was performed using the DFT/B3LYP/6-31G (d,p) method and showed that thiophene ring modifications can reduce the redox potential changing the reactivity and toxicity. All derivatives have better electrophilic properties and depends on the presence of nitro group. These results are confirmed by maps of electrostatic potentials and can indicated the most reactive regions that probable act on electrophilic attacks. Physicochemical parameters of nitazoxanide analogues were also evaluated using the DFT/B3LYP/6-31+G (d,p) method. A significant increase in the electron donating capacity for these new molecules from the HOMO, LUMO and GAP values was observed. An additional nitro group on ring structure beget compounds that have great stability and electron-accepting capacity. This electronic property is essential for biological activity on nitro compounds. The electrostatic potentials for nitazoxanide and its related analogues show the significant negative charge density on the nitro region. In addition, a conformational analysis of nitazoxanide, tizoxanide and a nitazoxamide derivatives was performed. The lower conformer of nitazoxanide agrees with the crystallographic structure. The more stable structures of the derivatives are related to their conformational similarity. The nitazoxanide molecule and three other derivatives have been synthesized and are available for biological evaluation on future works.
Acesso aberto (Open Access)
Planejamento e desenvolvimento de derivados do muscimol com propriedades antioxidantes
(Universidade Federal do Pará, 2019-12-09) SOUSA, Alanna Crystine Lima Farias de; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Muscimole is a psychoactive izoxazole compound extracted from mushrooms of the genus Amanita muscaria has been studied as a GABA inhibitor due to behavioral genes, since its structural structure is based on mammalian neurotransmitters GABA and glutamic acid. Due to its high selectivity and its own potential for neural activity, it is able to act as a drug, since it has a higher affinity for the GABAA receptor than GABA. Since the 1980s studies suggesting that GABA and muscimol are related to serotonin concentration, where increased GABA concentration or muscimol injection increases serotonin concentration and decreases inactive product after serotonin. oxidation, 5-HIAA. For this reason, this work aimed to plan and develop muscimol derivatives as an alternative for increase the serotonin using antioxidant activity. For this reason, this work aimed to plan and develop muscimole derivatives as an alternative for the treatment of anxiety and depression. For this, was used the drug planning method known as bioisosterism, which is characterized by being compounds or subunits of bioactive substances with similar structural characteristics, as well as similar physical and chemical properties with the ability to present analogous biological properties, can be agonists or antagonists. Firstly, a study was made of the groups that are responsible for the biological activity through the muscimole pharmacophores, where the groups that interact with the GABAA receptor are the -NH2 groupings, the isoxazole ring, as well as the oxygen present in the carbonyl. Then molecular modeling was performed, which was performed using the DFT B3LYP 6-311G (2d, 2p) method to verify the values of HOMO, LUMO, GAP, ionization potential (IP), bond energy dissociation, hydrogen atom transfer and single electron transfer, where it was found that the derivative S1 presented values equal -7.61 eV, -1.36 eV, -6.25 eV, 205.87.85 kcal/mol, 80.81 kcal/mol, -15.45 kcal/mol e -6.99 kcal/mol, respectively. The derivative S2 presented values of -6.80 eV, -1.08 eV, 5.72 eV, 198.41 kcal/mol, 77.73 kcal/mol, -18.53 kcal/mol e -0.47 kcal/mol, respectively. When compared with GABA, it was found that they are reactive, among which derivative S2 is more reactive, presenting lower GAP value compared to S1, and with PI values, it was found that derivative S1 has a lower electron donor capacity than derivative S2, highlighting that the best route is through the hydrogen donation mechanism. Then, the regioisomers derivatives were synthesized with a yield for S1 and S2 of 74,08% and 60,42%, respectively, as well as characterization through the melting point, where the derivative S1 had equal melting point. at 114,5 ° C - 115 ° C and S2, 182,5 ° C, showing that the synthesized molecules are pure, since they were compared with the data in the literature. With these data it is possible to say that muscimol derivatives have high antioxidant activity.
Acesso aberto (Open Access)
Planejamento e síntese de novos derivados da associação molecular benzonidazol e metronidazol
(Universidade Federal do Pará, 2018-09-25) COSTA, Fernanda Menezes; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Chagas disease is caused by protozoan Trypanosoma cruzi, still has high contagion rates in present days, especially in the Amazon region. After contamination, the infective cycle of Chagas disease has two phases: acute and chronic. The acute phase is, in majority of cases, asymptomatic and efficiently treated, however the chronic phase is symptomatic and has proved not efficient treatment. There is only one available medicine, the generic benznidazole or Rochagan®, distributed free of charge, and it must be administered for 60 days, approximately. However, benznidazole has low efficiency, being effective only on acute phase (asymptomatic). Besides that, the medicine use to cause severe side effects in clinical patients, producing in many times the treatment rejection. The molecular modeling has become an important tool on new drugs design, using the DFT method to evaluate of the new potent molecules. Thereby, the main goal of this work was to design new derivatives by using molecular modifications of benznidazole and metronidazole aiming to reduce their redox capacity. With this purpose, a theoretical study was performed of two benznidazole derivatives through molecular association and chain increase. From the theoretical study, this molecular association between benznidazole and metronidazole molecules can develop a less toxic new derivative of than benznidazole. Both designed derivatives were synthesized on laboratory using the classics methodologies of electrophilic and nucleophilic substitution, esterification, alkylation and nitration. According to their HOMO, LUMO, ionization potential, and electron affinity values, it was possible observe that the nibendazole 1 and nibendazole 2 compounds have a lower redox capacity when compared to benznidazole. The GAP values showed that the derivatives are less reactive than benznidazole. The HOMO and LUMO graphics, showed that the nitroimidazoles rings have high electron-withdrawing capacity as well as benzyl group has high electron-donating capacity. These properties change in accordance to methyl moiety or nitrogen positions on azolic ring of derivatives compounds.
Acesso aberto (Open Access)
Planejamento e síntese de novos derivados relacionados ao piroxicam
(Universidade Federal do Pará, 2019-12-09) OTA, Sirlene Sayuri Barros; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Piroxicam is a drug belonging to the group of oxicams, derived from phenolic acids, in the class of NSAIDs. Although not the drug of choice in some treatments, the drug is indicated for the treatment of acute musculoskeletal disorders, post-traumatic and postoperative pain, rheumatoid arthritis and osteoarthritis, primary dysmenorrhea, endometriosis and hemorrhagic cyst. Like non-steroidal anti-inflammatory drugs, piroxicam is able to inhibit prostaglandin synthesis from arachidonic acid by competitively reversible inhibition of COX activity, with some predominance to inhibit COX-2 activity. Photosensitivity is one of the adverse effects caused by the drug, being observed in about 1% of patients. In addition, various techniques have been used to improve the stability of piroxicam without diminishing its potential. Thus, the objective of this paper is to plan, synthesize and evaluate more stable derivatives related to the phototoxicity of the study drug. Calculations of electronic properties such as high energy occupied molecular orbital (HOMO), low energy occupied molecular orbital (LUMO) and ionization potential (IP), as well as reactivity index calculations (Mulliken, CHELPG and Fukui) were calculated. performed using the Gaussview and Gaussian 2009 packages. The proposed derivatives have been synthesized through classical reactions such as esterification and nucleophilic substitution and are in the process of purification. The results of the HOMO and LUMO values showed that the D4 molecule has a better electronic distribution, with the second lowest HOMO value and the highest LUMO value, and can be considered the most stable. The D6 molecule proved to be the most reactive derivative and this can be explained by the presence of two hydroxyls in the naphthalene ring of the derivative, influencing the reactivity of the molecule. Based on the GAP values, the nitrated derivative (D2) presented lower value (3.36 eV), indicating high reactivity. The D4 molecule presented the highest GAP value, confirming its stability. In the analysis of Mulliken, CHELPG and Fukui loads of piroxicam, differences in substitution orientation were observed, probably due to the difference in calculations performed for each index. In the theoretical results of the chemical reactivity study using UV-Vis, piroxicam and its naphthalenic derivative showed completely different profiles, referring to its three main peaks, being the most expressive in the C = C system, indicating that in the benzothiazine system it functions as a reactive alkene after energy absorption.Thus, the molecular modification by the naphthalene system presented a compound with higher chemical stability and lower reactivity.
Acesso aberto (Open Access)
Planejamento, síntese e aplicações de derivados naftosalicílicos como antioxidantes
(Universidade Federal do Pará, 2017-08-30) BARROS, Valéria Araújo; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/ 0000-0003-4072-7573
Salicylate derivatives are successfully applied as analgesics, antipyretics, anti-inflammatories and in cancer prevention, especially rectal colon. They reduce the risks of many diseases associated with elderly. However, adverse effects related to gastrointestinal events are always associated to its main constituent acetylsalicylic acid. These aspects are linked to their chemical stability and affinity for some biological receptors. The aims of this work are the design, synthesis and applications of naphthalene-salicylic derivatives as antioxidants. Thus, a theoretical study of the studied compounds was carried out. Calculations of electronic properties such as frontier orbitals HOMO-LUMO, ionization potential (IP), bond dissociation energy of phenolic moiety (BDEOH), and spin density contributions were performed by using density functional theory (DFT) at the B3LYP/6-31G (d, p) level of theory on Gaussview and Gaussian computational packages. Some of these compounds were synthesized by using classical methods. The theoretical results showed that both additional hydroxyl or substitution on benzene ring for naphthalene increase the antioxidant capacity in the same values with small dissimilarities among acid, ester, and amide derivatives. A synergistic effect was observed when both are used together, producing the most potent molecules. In addition, spin density calculations indicated a regioselective pathway can be gotten from monohydroxylic derivatives, with high possibility of in vivo generating of dihydroxy derivatives mainly at the para position relative to the phenolic group, through enzymatic or non-enzymatic reactions. Finally, the replacement of the naphthalene ring instead of the benzene ring increases both reactivity and chemical stability for the quinone-type intermediates, explaining how these compounds will play a role in the preventive mechanisms and way treatment of cancer. Anti cancer and anti-inflammatory activities are being performed for some of the synthesized compounds.
Acesso aberto (Open Access)
Planejamento, síntese e avaliação dos derivados da edaravona quanto à atividade antioxidante
(Universidade Federal do Pará, 2018-03-28) AIRES, Wanessa Castilho; OLIVEIRA, Karen Renata Matos; http://lattes.cnpq.br/3032008039259369; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/ 0000-0003-4072-7573
Edaravone is a commercial drug released on the Japanese Market, indicated in the treatment and prevention of ischemic stroke. Its action is due to its scavenger properties of free radical released in the ischemia. However, its use may lead to a kidney toxic effect. Therefore, in this work, a new bioisostere derivative from Edaravone was proposed, by the change of a pyrazolone ring for an indolone. Antioxidant properties was determined through computational methods. Calculations were undertaken in the software Gaussian, through the B3LYP method, with the set of bases 6-31G (d, p). Antioxidant activity was predicted from HOMO, LUMO, Gap, Ionization potential (IP) and Bond dissociation energy (BDE). Results indicate analogous compounds showed higher ClogP values compared to Edaravone, which means higher facility to pass through biological barriers, with higher liposoluble properties. Edaravone derivative, called Imidazone, also showed higher antioxidant potential than Edaravone. Methyl group in second position of heterocyclic ring was essential to more stable resonance structures formation to semiquinone form. All new derivatives proposed were extremely promising with antioxidant capacity superior to Edaravone.
Acesso aberto (Open Access)
Planejamento, Síntese, Avaliação das Propriedades Teóricas de orto-Regioisômeros Substituídos do Paracetamol
(Universidade Federal do Pará, 2018-12-28) MORAIS, Roberto Barbosa de; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Paracetamol is a clinically proven analgesic and antipyretic, which promotes analgesia by elevating the pain threshold and antipyretic through action in the hypothalamic center that regulates the temperature. Currently paracetamol is one of the medicines that is available in all the countries of the world in places related to health and can be acquired without prescription. Considered one of the most widely used drugs in the world as it is cheap and easy to access, it can also be used from birth to the elderly. Like non-steroidal anti-inflammatory drugs (NSAIDs) paracetamol is able to inhibit the synthesis of prostaglandins from arachidonic acid under specific conditions by inhibiting cyclooxygenase (COX). Although it is considered safe at therapeutic doses, Paracetamol has a toxicity attributed to one of its metabolic intermediates called N-acetyl-p-imine-benzoquinone (NAPQI), produced through enzymes present in cytochrome P450 (CYPE21). Thus, the objective of this present work is to plan, synthesize and evaluate possible antinociceptive and antipyretic activities of paracetamol analogues, ortacetamol and its derivatives in order to obtain a less toxic derivative. The calculations of electronic properties such as higher energy occupied molecular orbital (HOMO), lower energy unoccupied molecular orbital (LUMO), ionization potential (PI), phenolic bond dissociation energy (BDEOH) and spin densities were performed using the Gaussview and Gaussian 2009 packages. The values of the average values of BDENH, among others, are those that are observed with the quality of a heating cycle for the high speed with the possibility of a chelation defined by a hydrogen bond of the amide with the phenoxyl radical. Given the results it is possible that BDENH energy compounds may be less potent than hindering the action of CYP on oxidation to form toxic intermediates. A proposed chlorinated derivative was proposed and synthesized. It is in biological evaluation phase. Orthacetamol was more potent antioxidant than paracetamol. Experimental results are in aggrement with theoretical values. We conclude that ortcetamol may be a potentially safer bioactive candidate than paracetamol.

Navegar

Navegando Programa de Pós-Graduação em Química Medicinal e Modelagem Molecular - PPGQMMM/ICS por Orientadores "BORGES, Rosivaldo dos Santos"