scholarly journals Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines, Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3320
Author(s):  
Samvel N. Sirakanyan ◽  
Domenico Spinelli ◽  
Athina Geronikaki ◽  
Victor Kartsev ◽  
Elmira K. Hakobyan ◽  
...  

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.

2020 ◽  
Author(s):  
Silvia Acosta Gutiérrez ◽  
Igor Bodrenko ◽  
Matteo Ceccarelli

The lack of new drugs for Gram-negative pathogens is a global threat to modern medicine. The complexity of their cell envelope, with an additional outer membrane, hinders internal accumulation and thus, the access of molecules to targets. Our limited understanding of the molecular basis for compound influx and efflux from these pathogens is a major bottleneck for the discovery of effective antibacterial compounds. Here we analyse the correlation between the whole-cell compound accumulation of ~200 molecules and their predicted porin permeability coefficient (influx), using a recently developed scoring function. We found a strong linear relationship (75%) between the two, confirming porins key role in compound penetration. Further, the remarkable prediction ability of the scoring function demonstrates its potentiality to guide the optimization of hits to leads as well as the possibility of screening ultra-large virtual libraries. Eventually, the analysis of false positives, molecules with high-predicted influx but low accumulation, provides new hints on the molecular properties behind efflux.<br>


2021 ◽  
pp. 1-11
Author(s):  
Iris Cristina Maia Oliveira ◽  
Auriana Serra Vasconcelos Mallmann ◽  
Francisco Adelvane de Paula Rodrigues ◽  
Laura Maria Teodorio Vidal ◽  
Iardja Stéfane Lopes Sales ◽  
...  

<b><i>Background:</i></b> Depression is a common, chronic, and often recurrent serious mood disorder. Conventional antidepressants present limitations that stimulate the search for new drugs. Antioxidant and neuroprotective substances are potential antidepressant agents. In this context, riparin I (RIP I) has presented promising results, emerging as a potential source of a new therapeutic drug. In this study, the antidepressant effect of RIP I was evaluated in an animal model of depression induced by corticosterone (CORT). The involvement of neuroprotective and antioxidant mechanisms in the generation of this effect was also assessed. <b><i>Methods:</i></b> Female mice were submitted to CORT for 21 days and treated with RIP I in the last 7 days. Behavioral and neurochemical analyses were performed. <b><i>Results:</i></b> The administration of RIP I reversed the depressive and psychotic-like behavior, as well as the cognitive impairment caused by CORT, in addition to regulating oxidative stress parameters and BDNF levels in depression-related brain areas. <b><i>Conclusion:</i></b> These findings suggest that RIP I can be a strong candidate for drugs in the treatment of depression.


2018 ◽  
Vol 6 (5) ◽  
pp. 440-461
Author(s):  
O. L. Orlova ◽  
L. L. Nikolaeva ◽  
L. A. Korol ◽  
M. V. Dmitrieva ◽  
A. P. Polozkova ◽  
...  

Despite the development of biotherapy, chemotherapy remains one of the main methods of treatment of cancer patients. Currently, there are more than 100 anticancer drug substances, however, every year new drugs enter clinical practice and various therapeutic regimens are tested, expanding the possibilities of therapy and improving the results of treatment. Therefore, the adequate use of modern chemotherapy requires constant updating of information about anticancer drugs and methods of their use. Oral administration of drugs is the most natural and convenient way to introduce drugs into the human body. There are about 75% of orally administered drugs that have the ability to be absorbed in the gastrointestinal tract within 1−3 hours after administration. Oral dosage forms (DF) are most common due to the relative simplicity of their production, convenience of use, accuracy of dosing and high stability. Therefore, pharmaceutical companies often reproduce generics in the form of tablets and capsules for oral administration. However, most active pharmaceutical ingredient (API) are destroyed by the action of the gastrointestinal tract environment, which makes it impossible to use the oral administration. This review of the literature describes the main groups of anticancer drugs that are effective when taken orally.The aimof the study is to compile the information on the main groups of anticancer drugs used internally.Materials and methods.The object of the study was well-known anticancer drugs approved for oral administration. The study was conducted using search information and library databases (eLibrary, PubMed, CyberLeninka, ResearchGate), as well as State Register of Medicinal Remedies.Results and discussion.Analyzing the arsenal of cytotoxic drugs, it should be noted that antitumor substances are characterized by high chemical lability they are photosensitive, heat-labile, hygroscopic and hydrolytically unstable. These properties complicate both obtaining reproducible therapeutic effect when taken orally and technological inprocesses. In addition, anticancer drugs have mutagenic, teratogenic, sensitizing and allergenic effects.Conclusion.Lack of sufficient selectivity of the antitumor effect of cytotoxic drugs and a small breadth of pharmacological action require the use of DF, ensuring control of drug delivery to the body, including dosage accuracy and standard bioavailability. DF plays a very important role in the delivery of drugs to the lesion site. Capsules and coated tablets are necessarily created to avoid high toxicity of anticancer drugs and local tissue reactions when taken orally.


Author(s):  
Elizeu Pereira dos Santos ◽  
Fernanda Sodré Rodrigues ◽  
Islene Cristina Rabelo de Sousa Santos ◽  
Keylla Cristhianne de Sá Silva ◽  
Gizelli Santos Lourenço Coutinho ◽  
...  

A fitoterapia apresenta inúmeras possibilidades de tratamento, e tem se mostrado muito eficiente e um importante aliado para a medicina, cuja  utilização na área da saúde é crescente em função do  fato da busca constante de novos medicamentos com uma alta eficácia e baixa toxicidade, como é o caso da área odontológica, na qual se pode citar em específico a Punica granatum L. (romã). Assim, a finalidade deste trabalho é mostrar, através de pesquisas bibliográficas, a relevância do uso da espécie P. granatum na área odontológica, enfatizando seu potencial de eficácia como agente antimicrobiano sobre os micro-organismos do biofilme dental. Para isso, foi discutido sobre a importância da fitoterapia e da P. granatum na saúde bucal, além da sua aceitabilidade frente à realidade brasileira, fazendo algumas considerações sobre o biofilme dental e, também, sobre a ação antimicrobiana da espécie. Além disso, comparou-se o efeito da clorexidina com a romã, uma caracterização fitoquímica do extrato da romã, a partir da literatura científica e, por último, foi avaliada a eficácia e ação da P. granatum na saúde bucal em comparação com o gluconato de clorexidina. Com a pesquisa foi possível concluir que a ação farmacológica da P. granatum na odontologia é possível pela presença de seus importantes fitoconstituintes, que agem combatendo o biofilme bacteriano. Palavras-chave: Antimicrobiano. Biofilme. Fitoterapia. Romã. Saúde Bucal.  AbstractPhytotherapy has many possibilities for treatment, and has proven to be very efficient and an important ally for medicine, where its use in health is growing due to the constant search for new drugs with a high efficacy and low toxicity, as it is the case of the dental area, where it is possible to mention specifically Punica granatum L. (pomegranate). Thus, the aim of this work is to show through bibliographic research the relevance of the use of  P. granatum species in the dental area emphasizing its potential as an effective antimicrobial agent on the  dental biofilm microorganisms.Therefore,  the importance of phytotherapy and P. granatum in oral health were discussed, besides  their acceptability to the Brazilian reality, making some considerations about the dental biofilm and also about the species antimicrobial action. In addition, the effect of chlorhexidine with pomegranate was comapted, a phytochemical characterization of pomegranate extract from the scientific literature, and finally evaluated the efficacy and action of P. granatum in oral health compared to chlorhexidine gluconate. With the research it was possible to conclude that the  P. granatum pharmacological action in dentistry is possible due to the presence of its important phytochemicals that act against the bacterial biofilm. Keywords: Antimicrobial. Biofilm. Oral health. Phytotherapy. Pomegranate. 


2000 ◽  
Vol 65 (3) ◽  
pp. 475-487 ◽  
Author(s):  
Giovambattista De Sarro ◽  
Angelo Carotti ◽  
Francesco Campagna ◽  
Ruth Mckernan ◽  
Milena Rizzo ◽  
...  

1996 ◽  
Vol 31 (4) ◽  
pp. 335-339 ◽  
Author(s):  
J Guillon ◽  
M Daoust ◽  
D Radulovic ◽  
M Boulouard ◽  
P Dallemagne ◽  
...  

1985 ◽  
Vol 63 (11) ◽  
pp. 1477-1479 ◽  
Author(s):  
T. E. Fisher ◽  
D. D. Johnson ◽  
J. M. Tuchek ◽  
R. D. Crawford

Each of a series of benzodiazepines was found to be effective in preventing convulsions evoked by intermittent photic stimulation of epileptic chickens. There was a high correlation between the anticonvulsant potencies (mean effective dosages) and the affinity of the agents for the putative benzodiazepine receptor as measured by displacement of [3H]diazepam from binding sites on chicken synaptosomal membranes. This correlation in a genetic model of epilepsy provides further evidence that benzodiazepines exert their anticonvulsant effects by interacting with the benzodiazepine receptor.


ChemInform ◽  
2010 ◽  
Vol 27 (34) ◽  
pp. no-no
Author(s):  
J. GUILLON ◽  
M. DAOUST ◽  
D. RADULOVIC ◽  
M. BOULOUARD ◽  
P. DALLEMAGNE ◽  
...  

1983 ◽  
Vol 26 (6) ◽  
pp. 845-850 ◽  
Author(s):  
Robert J. Chorvat ◽  
Bipin N. Desai ◽  
Suzanne Evans Radak ◽  
James Bloss ◽  
James Hirsch ◽  
...  

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