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A cost-effective, selective, sensitive, and operational TLC-densitometric approach has been adapted for the concurrent assay of Hydroxyzine Hydrochloride (HYX), Ephedrine Hydrochloride (EPH), and Theophylline (THP) in their pure powder and pharmaceutical forms. In the innovative TLC-densitometric approach, HYX, EPH, and THP were efficaciously separated and quantified on a 60F254 silica gel stationary phase with chloroform-ammonium acetate buffer (9.5:0.5, v/v) adjusted to pH 6.5 using ammonia solution as a mobile liquid system and UV detection at 220 nm. The novel TLC method validation has been performed in line with the international conference for harmonization (ICH) standards and has been effectively used for the estimation of the researched medicines in their pharmaceutical formulations without intervention from excipients. Additionally, parameters affecting the chromatographic analysis have been investigated. The new TLC approach's functionality and greenness were appraised using three modern and automated tools, namely the Blue Applicability Grade Index (BAGI), the Analytical Greenness metric (AGREE), and the Green Analytical Procedure Index (GAPI) tools. In short, the greenness characteristics were not achieved as a result of using mandatory, non-ecofriendly solvents such as ammonia and chloroform. On the contrary, the applicability and usefulness of the novel TLC approach were attained via concurrent estimation for the three drugs using simple and straightforward procedures. Moreover, the novel TLC method outperforms previously published HPLC ones in terms of the short run time per sample and moderate pH value for the liquid system. According to the conclusions of comparisons with previously recorded TLC methods, our novel HPTLC method has the highest AGREE score, so it is the greenest HPTLC strategy. Moreover, its functionality and applicability are very appropriate because of the simultaneous assessment of three drugs in one TLC run. Furthermore, no tedious and complicated extraction and evaporation processes are prerequisites.
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Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors.
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Protein kinases (PKs) including RAF, perform a principal role in regulating countless cellular events such as cell growth, differentiation, and angiogenesis. Overexpression and mutation of RAF kinases are significant contributors to the development and spread of cancer. Therefore, RAF kinase inhibitors show promising outcomes as anti-cancer small molecules by suppressing the expression of RAF protein, blocking RAS/RAF interaction, or inhibiting RAF enzymes. Currently, there are insufficient reports about approving drugs with minimal degree of toxicity. Therefore, it is an urgent need to develop new RAF kinase inhibitors correlated with increased anticancer activity and lower cytotoxicity. This review outlines reported RAF kinase inhibitors for cancer treatment in patents and literature from 2019 to 2023. It highlights the available inhibitors by shedding light on their chemical structures, biochemical profiles, and current status. Additionally, we highlighted the hinge region-binding moiety of the reported compounds by showing the hydrogen bond patterns of representative inhibitors with the hinge region for each class. In recent years, RAF kinase inhibitors have gained considerable attention in cancer research and drug development due to their potential to be studied under clinical trials and their demonstration of various degrees of efficacy and safety profiles across different cancer types. However, addressing challenges related to drug resistance and safety represents a major avenue for the optimization and enhancement of RAF kinase inhibitors. Strategies to overcome such obstacles were discussed such as developing novel pan-RAF inhibitors, RAF dimer inhibitors, and combination treatments.
Assuntos
Antineoplásicos , Neoplasias , Inibidores de Proteínas Quinases , Quinases raf , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Quinases raf/antagonistas & inibidores , Quinases raf/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estrutura Molecular , Animais , Relação Estrutura-AtividadeRESUMO
Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.
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Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Piridinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Animais , Simulação de Acoplamento Molecular , CamundongosRESUMO
Considering the emergence of new anticancer drugs, in this review we emphasized and highlighted the recent reports and advances related to sulfamate-incorporating compounds with potential anticancer activity during the last 5 years (2020-2024). Additionally, we discussed their structure-activity relationship, clarifying their potent bioactivity as anticancer agents. Sulfamate derivatives hold promise as effective therapeutic candidates against cancer. By targeting biological targets associated with the development of cancer, such as steroid sulfatases (STS), carbonic anhydrases (CAs), microtubules, NEDD8-activating enzyme, small ubiquitin-like modifiers (SUMO)-activating enzyme (SAE), cyclin-dependent kinases (CDKs), breast cancer susceptibility gene 1 (BRCA1), and so on, this can furnish small molecules as anticancer lead candidates serving the drug discovery field. For example, compound 2, an STS inhibitor, demonstrated superior activity compared to its reference, irosustat, by fivefold. In addition, compound 21, an SAE, is under phase I clinical trials. Continued research into sulfamate derivatives holds potential for the development of novel therapeutic agents targeting various diseases.
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Managing primary amoebic meningoencephalitis, induced by Naegleria fowleri poses a complex medical challenge. There is currently no specific anti-amoebic drug that has proven effectiveness against N. fowleri infection. Ongoing research endeavours are dedicated to uncovering innovative treatment strategies, including the utilization of drugs and immune modulators targeting Naegleria infection. In this study, we explored the potential of imidazo[2,1-b]thiazole and imidazooxazole derivatives that incorporate sulfonate and sulfamate groups as agents with anti-amoebic properties against N. fowleri. We assessed several synthesized compounds (1f, 1m, 1q, 1s, and 1t) for their efficacy in eliminating amoebae, their impact on cytotoxicity, and their influence on the damage caused to human cerebral microvascular endothelial (HBEC-5i) cells when exposed to the N. fowleri (ATCC 30174) strain. The outcomes revealed that, among the five compounds under examination, 1m, 1q, and 1t demonstrated notable anti-parasitic effects against N. fowleri (P ≤ 0.05). Compound 1t exhibited the highest anti-parasitic activity, reducing N. fowleri population by 80%. Additionally, three compounds, 1m, 1q, and 1t, significantly mitigated the damage inflicted on host cells by N. fowleri. However, the results of cytotoxicity analysis indicated that while 1m and 1q had minimal cytotoxic effects on endothelial cells, compound 1t caused moderate cytotoxicity (34%). Consequently, we conclude that imidazo[2,1-b]thiazole and imidazooxazole derivatives containing sulfonate and sulfamate groups exhibit a marked capacity to eliminate amoebae viability while causing limited toxicity to human cells. In aggregate, these findings hold promise that could potentially evolve into novel therapeutic options for treating N. fowleri infection.
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Antiprotozoários , Células Endoteliais , Naegleria fowleri , Tiazóis , Humanos , Tiazóis/farmacologia , Tiazóis/química , Naegleria fowleri/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Linhagem Celular , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Oxazóis/farmacologia , Oxazóis/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise in managing type II diabetes. Nanomicelles were created by conjugating curcumin with chitosan through succinic anhydride. Succinyl-curcumin, the resultant compound, was esterified with chitosan to form a polymer prodrug conjugate. Nanomicelles, formed via dialysis, were spherical with a hydrodynamic size of 49.37 nm. In vitro release studies revealed 97% curcumin release at pH 5 in 7 days. A 21-day experiment on diabetic mice compared nanomicelles, standard drug, and free curcumin's impact on fasting blood glucose. The study showcased gradual, controlled curcumin release from nanomicelles, suggesting their potential in type II diabetes treatment.
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Quitosana , Curcumina , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Camundongos Endogâmicos BALB C , Micelas , Pró-Fármacos , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Quitosana/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Nanopartículas/química , Masculino , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/químicaRESUMO
Due to their susceptibility to degradation, vitamin levels in food formulations may differ from those found in the finished product. Vitamin levels can be impacted by processing and storage. In this work, the ingredients of Strong B50 ® film-coated tablets were estimated simultaneously using simple efficient stability indicating HPLC method. Strong B50 ® film-coated tablets contain thiamine (VB1), riboflavin (VB2), calcium pantothenate (VB5), pyridoxine (VB6), vitamin C (VC), folic acid (FA), biotin (BT), inositol (IS), niacin (NC), para-aminobenzoic acid (PB), cyanocobalamine (B12), choline bitartarate, and iron gluconate. Hypersil BDS C18 column was used for achieving reasonable separation. Mobile phases (A) and (B) were utilized, the mobile phase (A) consisted of 0.015 M Hexane sulfonic acid sodium salt + 0.1 % Triethylamine and orthophosphoric acid was used to adjust the pH to (2.9) while (B) system consisted of acetonitrile. Validation of the method was assessed using International Conference of Harmonization (ICH) parameters, where linearity, accuracy, selectivity, and robustness of the method were investigated. Correlations were above 0.99, accuracy results ranged from 97.6 to 102.8 % and limits for detection and quantitation (LOD and LOQ) values were determined for each vitamin in µg/mL except for FA and BT in ng/mL. LOD values were between 0.006 and 15.08 µg/mL while LOQ values ranged from 0.031 to 49.77 µg/mL. Stability studies were conducted under stressed conditions and degradation percentages were computed. Where, VB5, VB6, FA and PB, VC, and NC were the most degradable vitamins. Whiteness evaluation using the modern RGB 12 algorithm compared our method and the old reported one by Sasaki et al., 2020. The comparison favored our newly developed method in terms of analytical performance, practical applicability and greenness. Besides, AGREE and GAPI soft wares were used to assess the greenness of the method. It was clear that the results of colored pictograms confirm low hazardous impact and that the new method is greener with AGREE score of 0.66. Furthermore, the functionality and applicability of the novel HPLC approach were concluded via the Blue Applicability Grade Index (BAGI) tool with a final score of 82.5.
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Suplementos Nutricionais , Vitaminas , Cromatografia Líquida de Alta Pressão/métodos , Vitaminas/análise , Vitaminas/química , Suplementos Nutricionais/análise , Estabilidade de Medicamentos , Comprimidos , Limite de DetecçãoRESUMO
A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC50 value of 0.42 ± 0.08 µM, which is 53-fold more potent than thiourea, positive control (IC50 = 22.3 ± 0.031 µM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.
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Antibacterianos , Benzofuranos , Inibidores Enzimáticos , Helicobacter pylori , Simulação de Acoplamento Molecular , Ácidos Sulfônicos , Tiofenos , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Benzofuranos/química , Benzofuranos/farmacologia , Humanos , Tiofenos/química , Tiofenos/farmacologia , Desenho de Fármacos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Descoberta de DrogasRESUMO
All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI50 = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.
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Neoplasias da Mama , Cloridrato de Raloxifeno , Ácidos Sulfônicos , Humanos , Feminino , Cloridrato de Raloxifeno/farmacologia , Receptor alfa de Estrogênio , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Esteril-Sulfatase , Neoplasias da Mama/tratamento farmacológico , Moduladores de Receptor EstrogênicoRESUMO
Acanthamoeba are ubiquitously distributed in the environment and can cause infection of the central nervous system as well a sight-threatening eye infection. Herein, the potential anti-amoebic activity of a series of sulfonate/sulfamate derivatives against pathogenic A. castellanii was evaluated. These compounds were tested using several assays namely amoebicidal, adhesion, excystation, cytotoxic, and cytopathogenicity. Amoebicidal assays revealed that the selected compounds reduced amoebae viability significantly (P < 0.05), and exhibited IC50 values at two-digit micromolar concentrations. Sulfamate derivatives 1j & 1k inhibited 50% of amoebae at 30.65 µM and 27.21 µM, respectively. The tested compounds blocked amoebae binding to host cells as well as inhibited amoebae excystation. Notably, the selected derivatives exhibited minimal human cell cytotoxicity but reduced parasite-mediated host cell damage. Overall, our study showed that sulfamate derivatives 1j & 1k have anti-amoebic potential and offer a promising avenue in the development of potential anti-amoebic drug candidates.
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Acanthamoeba castellanii , Amebicidas , Humanos , Acanthamoeba castellanii/genética , Ácidos Sulfônicos/farmacologia , Alcanossulfonatos , GenótipoRESUMO
BACKGROUND: Breast cancer is the most common malignancy globally, and is considered a major cause of cancer-related death. Tremendous effort is exerted to identify an optimal anticancer drug with limited side effects. The quinoline derivative RIMHS-Qi-23 had a wide-spectrum antiproliferative activity against various types of cancer cells. METHODS: In the current study, the effect of RIMHS-Qi-23 was tested on MCF-7 breast cancer cell line to evaluate its anticancer efficacy in comparison to the reference compound doxorubicin. RESULTS: Our data suggest an anti-proliferative effect of RIMHS-Qi-23 on the MCF-7 cell line with superior potency and selectivity compared to doxorubicin. Our mechanistic study suggested that the anti-proliferative effect of RIMHS-Qi-23 against MCF-7 cell line is not through targeted kinase inhibition but through other molecular machinery targeting cell proliferation and senescence such as cyclophlin A, p62, and LC3. CONCLUSION: RIMHS-Qi-23 is exerting an anti-proliferative effect that is more potent and selective than doxorubicin.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Células MCF-7 , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Proliferação de Células , Doxorrubicina/farmacologia , Linhagem Celular TumoralRESUMO
BACKGROUND: COVID-19 has been associated with olfactory dysfunction in many infected patients. The rise of calcium levels in the nasal secretions plays an essential role in the olfaction process with a desensitization effect on the olfactory receptor neurons and a negative impact on the olfaction transmission. Ethylene diamine tetra acetic acid (EDTA) is a chelating agent that can bind free calcium in the nasal secretions, thereby reducing the adverse effects of calcium on olfactory function. OBJECTIVES: The objective of this work is to demonstrate the effect of intranasal EDTA on improving olfactory dysfunction following COVID-19. METHODS: Fifty patients with a history of COVID-19 and olfactory dysfunction that persisted for more than 6 months were enrolled in the current prospective randomized clinical trial. Participants were randomized into 2 equal groups. Twenty-five patients were treated with olfactory training only, while the remaining 25 patients received treatment with olfactory training and a topical nasal spray of ethylene diamine tetra acetic acid. The olfactory function was assessed before treatment and 3 months later using the Sniffin' Sticks test. Additionally, the determination of calcium level in the nasal secretions was performed using an ion-selective electrode before treatment and 3 months later. RESULTS: Eighty-eight percent of the patients treated with olfactory training in addition to EDTA exhibited clinical improvement, while 60% showed improvement in patients treated with olfactory training only. Furthermore, a significant decrease in the measured calcium level in the nasal secretions was demonstrated after the use of ethylene diamine tetra compared to patients treated with olfactory training only. CONCLUSION: Ethylene diamine tetra acetic acid may be associated with an improvement of the olfactory function post-COVID-19.
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COVID-19 , Transtornos do Olfato , Humanos , Olfato/fisiologia , Transtornos do Olfato/tratamento farmacológico , Transtornos do Olfato/etiologia , Ácido Acético/farmacologia , Ácido Acético/uso terapêutico , Cálcio/farmacologia , Cálcio/uso terapêutico , Ácido Edético/uso terapêutico , Ácido Edético/farmacologia , COVID-19/complicações , Etilenos/farmacologia , Etilenos/uso terapêuticoRESUMO
The glucosinolate-myrosinase system, exclusively found in the Brassicaceae family, is a main defense strategy against insect resistance. The efficient detoxification activity of glucosinolate sulfatases (GSSs) has successfully supported the feeding of Plutella xylostella on cruciferous plants. With the activity of GSSs hampered in P. xylostella, the toxic isothiocyanates produced from glucosinolates severely impair larval growth and adult reproduction. Therefore, inhibitors of GSSs have been suggested as an alternative approach to controlling P. xylostella. Herein, we synthesized eight adamantyl-possessing sulfamate derivatives as novel inhibitors of GSSs. Adam-20-S exhibited the most potent GSS inhibitory activity, with an IC50 value of 9.04 mg/L. The suppression of GSSs by Adam-20-S impaired glucosinolate metabolism to produce more toxic isothiocyanates in P. xylostella. Consequently, the growth and development of P. xylostella were significantly hindered when feeding on the host plant. Our study may help facilitate the development of a comprehensive pest management strategy that combines insect detoxification enzyme inhibitors with plant chemical defenses.
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Adamantano , Glucosinolatos , Animais , Glucosinolatos/farmacologia , Glucosinolatos/metabolismo , Insetos/metabolismo , Plantas/metabolismo , Sulfatases , Isotiocianatos/farmacologia , Isotiocianatos/metabolismoRESUMO
Imidazo[2,1-b]oxazole and 2,3-dihydroimidazo[2,1-b]oxazole ring systems are commonly employed in therapeutically active molecules. In this article, the authors review the utilization of these core scaffolds as chemotherapeutic agents from 2018 to 2022. These scaffolds possess many important biological activities including antimicrobial and anticancer, among others. This review covers their biological activities and structure-activity relationships. One of the most important drugs in this class of compounds is the antitubercular agent delamanid. In this paper, the compounds structure-activity relationship and preclinical and clinical trial data are thoroughly presented.
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Antituberculosos , Oxazóis , Oxazóis/farmacologia , Antituberculosos/farmacologia , Relação Estrutura-AtividadeRESUMO
Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder that affects women of reproductive age. It is characterized by abnormal production of androgens, typically present in small quantities in females. This study aimed to investigate the therapeutic potential of Irosustat (STX64), STX140, and compound 1G as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. 36 rats were divided into six groups of equal size. PCOS was induced in all groups, except the normal control group, by administering letrozole orally (1 mg/kg/day for 35 days). The onset of abnormal estrous cycle was confirmed by examining daily vaginal smears under a microscope. Subsequently, each rat group was assigned to a different treatment regimen, including one control group, one letrozole group, one metformin group (500 mg/kg/day) as a reference drug, and the other groups received a different drug candidate orally for 30 days. After treatment, blood collection was performed for biochemical measurements and determination of oxidative stress markers. The rats were dissected to separate ovaries and uterus for morphological, histological, and western blotting studies. Treatment with the drug candidates improved the ovaries and uterus weight measurements compared to the untreated PCOS group. The three tested drug candidates demonstrated promising improvements in lipid profile, blood glucose level, testosterone, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels. In addition, western blotting confirmed their promising effects on Akt, mTOR, and AMPK-α pathways. This study led to the discovery of three promising drug candidates for the management of PCOS as alternatives to metformin.
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Metformina , Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Metformina/efeitos adversos , Letrozol/efeitos adversos , Ratos WistarRESUMO
A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI50 of 1.28 µM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC50 of 2.81 µM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC50 of 4.82 µM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.
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Azóis , Proteínas Quinases JNK Ativadas por Mitógeno , Animais , Chlorocebus aethiops , Células Vero , Azóis/farmacologia , Isoformas de Proteínas , Piridinas/farmacologia , Proliferação de CélulasRESUMO
Naegleria fowleri is a free-living thermophilic flagellate amoeba that causes a rare but life-threatening infection called primary amoebic meningoencephalitis (PAM), with a very high fatality rate. Herein, the anti-amoebic potential of carboxamide derivatives possessing sulfonyl or sulfamoyl moiety was assessed against pathogenic N. fowleri using amoebicidal, cytotoxicity and cytopathogenicity assays. The results from amoebicidal experiments showed that derivatives dramatically reduced N. fowleri viability. Selected derivatives demonstrated IC50 values at lower concentrations; 1j showed IC50 at 24.65 µM, while 1k inhibited 50% amoebae growth at 23.31 µM. Compounds with significant amoebicidal effects demonstrated limited cytotoxicity against human cerebral microvascular endothelial cells. Finally, some derivatives mitigated N. fowleri-instigated host cell death. Ultimately, this study demonstrated that 1j and 1k exhibited potent anti-amoebic activity and ought to be looked at in future studies for the development of therapeutic anti-amoebic pharmaceuticals. Further investigation is required to determine the clinical relevance of our findings.
Assuntos
Amebicidas , Amoeba , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Humanos , Células Endoteliais , Amebicidas/farmacologia , Encéfalo/patologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológicoRESUMO
BACKGROUND: Ritonavir was recently combined with nirmatrelvir in a new approved co-packaged medication form for the treatment of COVID-19. Quantitative analysis based on fluorescence spectroscopy measurement was extensively used for sensitive determination of compounds exhibited unique fluorescence features. OBJECTIVE: The main objective of this work was to develop higher sensitive cost effective spectrofluorometric method for selective determination of ritonavir in the presence of nirmatrelvir in pure form, pharmaceutical tablet as well as in spiked human plasma. METHODS: Ritonavir was found to exhibit unique native emission fluorescence at 404 nm when excited at 326 nm. On the other hand, nirmatrelvir had no emission bands when excited at 326 nm. This feature allowed selective determination of ritonavir without any interference from nirmatrelvir. The variables affecting fluorescence intensity of ritonavir were optimized in terms of sensitivity parameters and principles of green analytical chemistry. Ethanol was used a green solvent which provided efficient fluorescence intensity of the cited drug. RESULTS: The method was validated in accordance with the ICH Q2 (R1) standards in terms of linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and specificity. The described method was successfully applied for ritonavir assay over the concentration range of 2.0-20.0 ng/mL. CONCLUSION: Ritonavir determination in the spiked human plasma was successfully done with satisfactory accepted results.