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1.
Int J Pharm ; 609: 121191, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670120

RESUMO

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery.


Assuntos
Hipertensão , Pró-Fármacos , Animais , Captopril , Sistemas de Liberação de Medicamentos , Hipertensão/tratamento farmacológico , Lipossomos , Tamanho da Partícula , Quercetina , Ratos
2.
Bioorg Med Chem ; 50: 116458, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34687983

RESUMO

Parasitic diseases remain a major public health concern for humans, claiming millions of lives annually. Although different treatments are required for these diseases, drug usage is limited due to the development of resistance and toxicity, which necessitate alternative therapies. It has been shown in the literature that parasitic lactate dehydrogenases (LDH) and malate dehydrogenases (MDH) have unique pharmacological selective and specificity properties compared to other isoforms, thus highlighting them as viable therapeutic targets involved in aerobic and anaerobic glycolytic pathways. LDH and MDH are important therapeutic targets for invasive parasites because they play a critical role in the progression and development of parasitic diseases. Any strategy to impede these enzymes would be fatal to the parasites, paving the way to develop and discover novel antiparasitic agents. This review aims to highlight the importance of parasitic LDH and MDH as therapeutic drug targets in selected obligate apicoplast parasites. To the best of our knowledge, this review presents the first comprehensive review of LDH and MDH as potential antiparasitic targets for drug development studies.


Assuntos
Antiparasitários/farmacologia , Desenvolvimento de Medicamentos , L-Lactato Desidrogenase/antagonistas & inibidores , Malato Desidrogenase/antagonistas & inibidores , Animais , Antiparasitários/síntese química , Antiparasitários/química , Cryptosporidium parvum/efeitos dos fármacos , Cryptosporidium parvum/enzimologia , Humanos , L-Lactato Desidrogenase/metabolismo , Malato Desidrogenase/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , Schistosoma/efeitos dos fármacos , Schistosoma/enzimologia , Toxoplasma/efeitos dos fármacos , Toxoplasma/enzimologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/enzimologia
3.
Bioorg Chem ; 115: 105133, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34329993

RESUMO

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Hidrazonas/química , Isatina/química , Morfolinas/química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Antituberculosos/metabolismo , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , DNA Girase/química , DNA Girase/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Hidrazonas/metabolismo , Hidrazonas/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Rifampina/farmacologia , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 217: 113330, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744688

RESUMO

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N'-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds. The antiplasmodial screening revealed that seven analogues showed promising to good activity with half-maximal inhibitory concentration (IC50) = 0.32 µM-4.30 µM. Compound 7a with 1,4-diamine butyl linker and 4-hydroxyl phenyl on fourth and sixth position of pyrimidine core showed the most prominent activity with an IC50 value of 0.32 ± 0.06 µM, with a favourable safety profile of 9.79 to human kidney epithelial (HEK293) cells. The remaining six analogues showed moderate activity with IC50 values ranging from 7.50 µM to 83.01 µM. We further investigated the binding affinities of the molecules to two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z. Compound 7a exhibited the highest binding affinity for both PfHsp70s with KD in a lower nanomolar range (4.4-11.4 nM). Furthermore, molecular docking revealed that compounds 6, 6k, 7b and 7a exhibited better fitness in PfHsp70-1 with compound 7a showing the highest and lowest binding scores of -9.8 kcal/mol. Therefore, we speculate that PfHsp70-1 is one of the targets of these inhibitors. The bioisoteric replacement of the groups at phenyl ring at the fourth and sixth position of the pyrimidine core had a constructive association with antiplasmodial activity. The promising antiplasmodial activity of the synthesised analogues illustrates how crucial molecular hybridisation is as a strategy in the development of quinoline-pyrimidine hybrids as prospective antiprotozoal agents.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacologia , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirimidinas/química , Quinolinas/química , Relação Estrutura-Atividade , Termodinâmica
5.
Mater Sci Eng C Mater Biol Appl ; 97: 285-292, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30678913

RESUMO

A glassy carbon electrode modified with electrochemically polymerized methyl orange (PMO) and multi-walled carbon nanotubes (MWCNT) was developed. The morphologies of the fabricating materials (PMO and MWCNT) were investigated by field-emission scanning electron microscopy (FE-SEM). The designed sensor was used for the sensitive determination of amodiaquine (AQ), an anti-malaria drug. AQ was developed as an alternative to chloroquine because of its activity against chloroquine-resistant Plasmodium falciparum (P. falciparum) parasites. The modified electrode was employed to study the electrochemical oxidation of AQ using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. Under optimal experimental conditions, DPV exhibited a linear response in the concentration range from 1.0 × 10-7 to 3.5 × 10-6 mol L-1 with a limit of detection (LOD) of 8.9 × 10-8 mol L-1. Furthermore, the number of electrons and protons involved in the electrochemical study of AQ was also calculated and a plausible mechanism for the electro-oxidation of AQ was deduced. The developed sensor demonstrated analytical applicability as it was successfully employed to determine the drug AQ in pharmaceutical formulations and human urine samples.


Assuntos
Amodiaquina/análise , Antimaláricos/análise , Compostos Azo/química , Técnicas Eletroquímicas/instrumentação , Nanotubos de Carbono/química , Polímeros/química , Amodiaquina/urina , Antimaláricos/urina , Corantes/química , Técnicas Eletroquímicas/métodos , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Oxirredução , Sensibilidade e Especificidade , Comprimidos
6.
Bioorg Med Chem ; 26(2): 309-339, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29273417

RESUMO

Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenosina/antagonistas & inibidores , Adenosina/metabolismo , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Citocininas/antagonistas & inibidores , Citocininas/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química
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