Neuroprotective effect and mechanism of celastrol and its derivatives in vitro / 中国药房

OBJECTIVE To explore the neuroprotective effect and possible mechanism of celastrol （Cel） and its derivatives （Cel-1， Cel-2） in terms of neuroinflammation and oxidative damage. METHODS Neuroinflammation model of microglial BV2 cells was induced by 1 μg/mL lipopolysaccharide （LPS）； oxidative damage model of human neuroblastoma SH-SY5Y cells was induced by 200 μmol/L hydrogen peroxide （H2O2）. The toxicity of different concentrations of Cel， Cel-1 and Cel-2 （0.625-20 μmol/L） to the two types of cells was investigated. The levels of nitric oxide （NO）， tumor necrosis factor α （TNF-α）， interleukin 1β （IL-1β）， and IL-6 in BV2 cells induced by LPS at safe concentrations （0.039-0.625 μmol/L） were all detected. The survival rate of SH-SY5Y cells induced by H2O2 was also determined. The expression levels of phosphoinositide 3-kinase （PI3K）， p-PI3K， protein kinase B （Akt）， p-Akt， cystatinase 3 （caspase-3）， B-cell lymphoma 2 （Bcl-2） and Bcl-2-related X protein （Bax） in SH- SY5Y cells induced by H2O2 at 0.156， 0.313， 0.625 μmol/L of active compound 2 were all detected. RESULTS In the concentration gradient range between 0.039 and 0.625 μmol/L， the results of neuroinflammation model experiments showed that Cel， Cel-1 and Cel-2 could reduce the contents of NO， TNF-α， IL-1β， and IL-6 in culture medium of BV2 cells （P＜0.05 or P＜ 0.01）； their IC50 values for neuroinflammation were （0.25±0.04）， （0.61±0.14） and （0.11±0.02） μmol/L respectively. Meanwhile， all of them could reverse the phenomenon of decreased cell survival rate after H2O2 treatment in the oxidative damage experiments at a certain concentration （P＜ 0.05 or P＜0.01）， with neuroprotective EC50 values of （0.43± XJC2023009） 0.08）， （0.45±0.04） and （0.28±0.03） μmol/L， respectively.Induced by H2O2， the phosphorylation of PI3K and Akt protein， protein expressions of Bcl-2 and Bcl-2/Bax ratio were all increased significantly （P＜0.05 or P＜0.01）， while the protein expressions of caspase-3 and Bax were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Cel， Cel-1， and Cel-2 all have significant neuroprotective activities at certain concentrations， and Cel-2 shows the most significant protective effect. The mechanism of action of Cel-2 may be related to regulating the PI3K/Akt and caspase-3/Bcl-2/Bax signaling pathways， reducing the inflammatory response， oxidative stress damage and inhibiting neuronal apoptosis.

A review of structural modification and biological activities of oleanolic acid / 中国天然药物

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.

Synthesis and evaluation of 2-phenylamino-1,4-naphthoquinones derivatives as potential hypoglycaemic agents

Abstract Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of chloro group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Resumo Em razão dos graves efeitos colaterais causados pela maioria dos medicamentos antidiabéticos atualmente utilizados, continua a busca por novos medicamentos seguros para o controle do diabetes. As naftoquinonas, que possuem fortes propriedades antioxidantes, têm sido empregadas como candidatas à terapia do diabetes. O presente estudo visa encontrar o potencial antioxidante e hipoglicemiante de alguns novos derivados de 2-fenilamino-1,4-naftoquinonas (PAN), incluindo derivados de cloro, nitro, metil e bromo (5a-d) sintetizados por experimento em pote único. Os cristais do produto foram purificados por TLC e caracterizados por FT-IR. O potencial antioxidante dos compostos foi testado por meio de atividades de sequestro de radicais DPPH e redução de energia observada como absorção no UV-vis. O ensaio DPPH mostrou a poderosa atividade antioxidante dos derivados nitro e bromo, enquanto o derivado nitro mostrou o potencial de redução significativo para o ensaio FRAP. O potencial hipoglicêmico dos compostos foi estudado em modelo animal de rato. Todos os compostos sintetizados revelaram melhor atividade hipoglicemiante; no entanto, o derivado cloro apresentou atividade hipoglicêmica mais potente, com redução de 43% nos níveis médios de glicose no sangue dos animais tratados. Como a biorredução de naftoquinonas pode ser influenciada pela alteração de suas propriedades redox, notou-se que o efeito da doação eletrônica por ressonância (+R) do grupo cloro tem sido significativo na atividade biológica por meio da estabilização de sua forma imina, que limita o potencial de geração de radicais livres durante a biorredução de quinonas, e, portanto, tem sido proposto como a razão de sua atividade hipoglicemiante. Estudos futuros empregando as propriedades de grupos de doação eletrônica de PAN podem otimizar a interação droga-receptor para melhor planejamento de medicamentos e estratégias de desenvolvimento de medicamentos contra o diabetes e também para os ensaios clínicos.

Synthesis and evaluation of 2-phenylamino-1, 4-naphthoquinones derivatives as potential hypoglycaemic agents / Síntese e avaliação de derivados de 2-fenilamino-1, 4-naftoquinonas como potenciais agentes hipoglicemiantes

Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of 'chloro' group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Em razão dos graves efeitos colaterais causados pela maioria dos medicamentos antidiabéticos atualmente utilizados, continua a busca por novos medicamentos seguros para o controle do diabetes. As naftoquinonas, que possuem fortes propriedades antioxidantes, têm sido empregadas como candidatas à terapia do diabetes. O presente estudo visa encontrar o potencial antioxidante e hipoglicemiante de alguns novos derivados de 2-fenilamino-1,4-naftoquinonas (PAN), incluindo derivados de cloro, nitro, metil e bromo (5a-d) sintetizados por experimento em pote único. Os cristais do produto foram purificados por TLC e caracterizados por FT-IR. O potencial antioxidante dos compostos foi testado por meio de atividades de sequestro de radicais DPPH e redução de energia observada como absorção no UV-vis. O ensaio DPPH mostrou a poderosa atividade antioxidante dos derivados nitro e bromo, enquanto o derivado nitro mostrou o potencial de redução significativo para o ensaio FRAP. O potencial hipoglicêmico dos compostos foi estudado em modelo animal de rato. Todos os compostos sintetizados revelaram melhor atividade hipoglicemiante; no entanto, o derivado cloro apresentou atividade hipoglicêmica mais potente, com redução de 43% nos níveis médios de glicose no sangue dos animais tratados. Como a biorredução de naftoquinonas pode ser influenciada pela alteração de suas propriedades redox, notou-se que o efeito da doação eletrônica por ressonância (+R) do grupo "cloro" tem sido significativo na atividade biológica por meio da estabilização de sua forma imina, que limita o potencial de geração de radicais livres durante a biorredução de quinonas, e, portanto, tem sido proposto como a razão de sua atividade hipoglicemiante. Estudos futuros empregando as propriedades de grupos de doação eletrônica de PAN podem otimizar a interação droga-receptor para melhor planejamento de medicamentos e estratégias de desenvolvimento de medicamentos contra o diabetes e também para os ensaios clínicos.

Fentanyl and other New Psychoactive Synthetic Opioids. Challenges to Prevention and Treatment

ABSTRACT Synthetic opioids have played a significant role in the current opioid crisis in the United States (U.S.) and Canada and are a matter of concern worldwide. New psychoactive opioids (NPOs) are classified in the internationally recognized new psychoactive substances (NPSs) category. This group comprises compounds that may have been synthesized decades ago but appeared only recently in the illicit drug market. Such is the case of fentanyl, fentanyl analogs, and non-fentanyl opioids. Most NPOs have effects similar to morphine, including euphoria and analgesia, and can produce fatal respiratory depression. Here, we present an overview of the systemic and molecular effects of main NPOs, their classification, and their pharmacological properties. We first review the fentanyl group of NPOs, including the four compounds of clinical use (fentanyl, alfentanil, sufentanil, and remifentanil) and the veterinary drug carfentanil. We also provide essential information on non-medical fentanyl analogs and other synthetic opioids such as brorphine, etonitazene, and MT-45, used as adulterants in commonly misused drugs. This paper also summarizes the scarce literature on the use of NPOs in Mexico. It concludes with a brief review of the challenges to prevention and treatment posed by NPOs and some recommendations to face them.

Síntesis y actividad antiproliferativa de una mezcla de derivados de (+/_) 7-clo-ro-(4-tioalquilquinolina). Inducción de apoptosis y daño sobre el ADn/aRN

Después de las enfermedades cardiovasculares, el cáncer, una patología no transmisible, ha sido considerado como la segunda causa de muertes cada año a nivel global y como la barrera más importante para aumentar la esperanza de vida en el siglo 21. Se han alcanzado avances de gran relevancia en su prevención y tratamiento; sin embargo, existe aún un largo camino por recorrer para alcanzar un tratamiento efectivo para cada tipo de cáncer. En este trabajo se describen enfoques de reposicionamiento y síntesis de moléculas híbridas con potencial actividad antineoplásica. Para obtener el al-dehído intermediario clave, se empleó la metodología de oxidación de Dess-Martin, que fue acoplado con las cetonas correspondientes usando LDA; se generó así una mezcla racémica para cada uno de los compuestos híbridos propuestos. La actividad antiproliferativa in vitro de los compuestos finales se evaluó frente a ocho líneas celulares derivadas de tumores sólidos humanos, y cuatro líneas celulares no cancerosas. El compuesto 11d resulto ser el más efectivo y con mayor índice de seguridad. Los resultados sugirieron que estos compuestos podrían bloquear el ciclo celular e inducir la apop-tosis y la muerte en las células CCRF-CEM de forma dependiente de la dosis in vitro.

After cardiovascular diseases, cancer, a non-communicable pathology, has been considered the second cause of death each year globally and as the most important barrier to increasing life expectancy in the 21st century. Advances of great relevance have been made in its prevention and treatment, however, there is still a long way to go to achieve an effective treatment for each type of cancer. This paper describes approaches to reposition and synthesis of hybrid molecules with potential antineoplastic activity. To obtain the key intermediate aldehyde, the Dess-Martin oxidation methodology was used, which was coupled with the corresponding ketones using LDA. The final hybrid compounds were obtained as a racemic mixture. The in vitro antiproli-ferative activity of the final compounds was evaluated against eight cell lines derived from human solid tumors, and four non-cancerous cell lines. The compound 11d turned out to be the most effective and with the highest safety index. The results suggested that these compounds could block the cell cycle and induce apoptosis and death in CCRF-CEM cells in a dose-dependent manner in vitro.

Depois das doenças cardiovasculares, o câncer, uma patologia não transmissível, tem sido considerado como a segunda causa de mortes a cada ano em todo o mundo e como a barreira mais importante para o aumento da expectativa de vida no século 21. Avanços de grande relevância têm sido feitos na sua prevenção e tratamento, no entanto, ainda há um longo caminho a percorrer para alcançar um tratamento eficaz para cada tipo de câncer. Este artigo descreve abordagens para o reposicionamento e síntese de moléculas híbridas com potencial atividade antineoplásica. Para a obtenção do aldeído intermediário chave, foi utilizada a metodologia de oxidação de Dess-Martin, que foi acoplada com as cetonas correspondentes usando LDA. Os compostos híbridos finais foram obtidos como uma mistura racêmica. A atividade antiproliferativa in vitro dos compostos finais foi avaliada contra oito linhagens celulares derivadas de tumores sólidos humanos e quatro linhagens celulares não cancerosas. O composto 11d revelou-se o mais eficaz e com o maior índice de segurança. Os resultados sugeriram que estes compostos poderiam bloquear o ciclo celular e induzir apoptose e morte em células CCRF-CEM de forma dose-de-pendente in vitro.

An-overview-on-the-biological-activities-of-pyrazole

The purpose of this study is to provide a summary of the various pyrazole moieties' pharmacological actions. Pyrazole is a well-known and essential nitrogen-containing 5-membered heterocyclic compound, and different techniques for synthesis have been developed. Pyrazole, also known chemically as 1, 2-diazole, has become a prominent subject due to its numerous applications. Numerous pyrazole derivatives have been discovered to have a wide range of biological functions, which has fueled study in this area. Pyrazoles and their variants are among the most powerful groups of chemicals, with anti-bacterial, anti-convulsant, analgesic, anti-microbial, anti-inflammatory, anti-diabetic, sedative, anti- rheumatic, anticancer, and anti-tubercular properties. The goal of this study was to compile literary work on pyrazole for its different pharmacological activities, as well as to report on new efforts made on this moiety.

Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection / 药物分析学报

On December 22,2021,the United States Food and Drug Administration approved the first main protease inhibitor,i.e.,oral antiviral nirmatrelvir(PF-07321332)/ritonavir(Paxlovid),for the treatment of early severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Nirmatrelvir inhibits SARS-CoV-2 infection,but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression.The chiral structure of nirmatrelvir plays a key role in its antiviral activity.Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites.Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir.However,Paxlovid has many contraindications.Some patients treated with Paxlovid experience a second round of coronavirus disease 2019(COVID-19)symptoms soon after re-covery.Interestingly,the antiviral activity of nirmatrelvir metabolites,such as compounds 12-18,is similar to or higher than that of nirmatrelvir.Herein,we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.

Research progress of anti-tumor effect and mechanism of CDDO and its derivatives / 中国药房

2-cyano-3，12-dioxooleana-1，9 （11）-dien-28-oic acid （CDDO） is a compound synthesized by taking oleanolic acid， a natural triterpene， as a precursor or precursor， and transforming three modifiable functional groups in the molecule through a series of chemical structure modification. In order to improve its anti-tumor activity， CDDO derivatives are further synthesized. In this paper， the research results of anti-tumor effects and mechanisms of CDDO and its derivatives in recent years are summarized. It is found that CDDO and its derivatives have a wide range of anti-tumor effects， and can show significant anti-tumor effects on breast cancer， pancreatic cancer， lung cancer and ovarian cancer at low concentrations such as micromole or even nanomole， among which CDDO methyl ester compound （CDDO-Me） and CDDO imidazolidinone compound （CDDO-Im） have the most obvious effects. CDDO and its derivatives exert anti-tumor activity mainly by inducing tumor cell apoptosis， and regulating metabolic reprogramming and immune microenvironment. The involved pathways mainly include Janus protein tyrosine kinase （JAK）/ signal transduction and transcription activation protein 3（STAT3） signal pathway， nuclear factor E2-related factor 2 （NRF2） signal pathway， phosphatidylinositol 3 kinase （PI3K）/protein kinase B （also known as Akt）/mammalian rapamycin target protein （mTOR） signal pathway， Wnt/β-catenin signal pathway， nuclear factor κB signal pathway.

Advances in stem cells treatment of androgenetic alopecia / 中国药科大学学报

@#Androgenetic alopecia (AGA) is the most prominent type of progressive hair loss in humans.At present, medication is the main treatment for AGA, however, drug therapy has significant side-effects. Stem cells provide a new strategy for the treatment of AGA, because of their role in tissue repair and maintenance of microenvironmental homeostasis.This paper reviews the pathogenesis of AGA, discusses the defects of traditional drug therapy,and discusses the research progress of stem cells and stem cell derivatives in the treatment of AGA, in order to provide a comprehensive review of the prospects of stem cell therapy for AGA.

Potential Medicinal Value of Rhein for Diabetic Kidney Disease / 中国结合医学杂志

Diabetic kidney disease (DKD) is the primary cause of mortality among diabetic patients. With the increasing prevalence of diabetes, it has become a major concern around the world. The therapeutic effect of clinical use of drugs is far from expected, and therapy choices to slow the progression of DKD remain restricted. Therefore, research on new drugs and treatments for DKD has been a hot topic in the medical field. It has been found that rhein has the potential to target the pathogenesis of DKD and has a wide range of pharmacological effects on DKD, such as anti-nephritis, decreasing blood glucose, controlling blood lipids and renal protection. In recent years, the medical value of rhein in the treatment of diabetes, DKD and renal disease has gradually attracted worldwide attention, especially its potential in the treatment of DKD. Currently, DKD can only be treated with medications from a single symptom and are accompanied by adverse effects, while rhein improves DKD with a multi-pathway and multi-target approach. Therefore, this paper reviews the therapeutic effects of rhein on DKD, and proposes solutions to the limitations of rhein itself, in order to provide valuable references for the clinical application of rhein in DKD and the development of new drugs.

Research progress of artemisinin and its derivatives in prevention and treatment of cardiovascular diseases / 中国药房

Artemisinin is a sesquiterpene lactone containing a peroxide group isolated from the plant Artemisia annua. It has antimalarial activity and is effective for the treatment of malaria. With the deepening of research on artemisinin， the pharmacological effects of artemisinin and its derivatives in other systems have gradually become a research hotspot. This article reviews the research progress of artemisinin and its derivatives in the prevention and treatment of cardiovascular diseases. Artemisinin and its derivatives in the prevention and treatment of cardiovascular disease have shown anti-atherosclerosis， lipid- lowering， inhibition of vascular remodeling， reducing vascular pressure， improving ventricular remodeling， anti-arrhythmia， protection of vascular endothelium， prevention and treatment of diabetic cardiovascular complications and protection of myocardial cells and other pharmacological effects. It provides a new treatment strategy for common cardiovascular diseases such as hypertension， arrhythmia， coronary heart disease complications after stent implantation， hyperlipidemia， etc. However， there are few studies on the antiplatelet aggregation and antithrombotic effects of artemisinin and its derivatives， the molecular mechanisms behind many pharmacological effects have not yet been clarified， and there is little clinical application. A large number of basic studies and clinical trials are still needed to answer these questions.

Two Cases of Plantar Keratosis Successfully Improved by Intake of Food Containing Hot Water Extract of Coix lacryma-jobi L. var. ma-yuen Stapf with Husks / 日本補完代替医療学会誌

We reported 2 cases of plantar keratosis (59 years of age, female/39 years of age, male) successfully improved by intake of hot water extract of Coix lacryma-jobi L. var. ma-yuen Stapf with Husks. Both subjects were administered coix seed extract containing food for 20 weeks. The lesions improved gradually after 12 weeks, and almost cured by 20 weeks of administration. Although the food seemed to be effective in these cases, further studies are needed to define the optimal dose and duration.

Design, synthesis and biological evaluation of 8-hydroxyquinoline derivatives as potential clostridium difficile antibiotics / 药学实践杂志

Objective To find a more effective alternative therapy for antibiotic therapy and fecal microbiota transplantation in current primary treatment of clostridioides difficile infection (CDI) because of the high recurrence rate. Methods A series of 8-hydroxyquinoline derivatives were designed and synthesized based on 8-hydroxyquinoline scarffold. Results The activity test against C. difficile showed that most of the molecules exhibited good antibacterial activity against C. difficile, and compound 6f showed attractive anti-C. difficile activity. Conclusion A new type of 8-hydroxyquinoline derivatives with anti-clostridium difficile was found, which could be used as good lead compounds for further development.

Synthesis and antifungal evaluation of chalcone derivatives combined with fluconazole against drug-resistant Candida albicans / 中国药科大学学报

@#Chalcone is a common scaffold in natural products with optimal properties and biological activities.In this study, we designed and prepared eight new coumarin-chalcone derivatives (5a-5h), and confirmed their structures by 1H NMR and 13C NMR. Their in vitro antifungal activity combined with fluconazole (FLC) against drug-resistant Candida albicans was tested by microdilution method.The results indicated that most chalcone derivatives showed good antifungal activity against drug resistant Candida albicans with FLC, particularly with compound 5g displaying better antifungal activity (MIC50 = 5.60 μg/mL) than FLC (MIC50 = 200 μg/mL) when combined with FLC, so, these derivatives could be used as synergists of antifungal drugs.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Design, synthesis and antifungal activity of novel triazoles containing propyl side chains / 药学实践杂志

Objective To study the antifungal activity of a new series of triazole compounds with n-propyl side chain and disubstituted benzyl structure. Methods Eleven target compounds were designed and synthesized. The structures were confirmed by 1H NMR, and some compounds were confirmed by 13C NMR or HRMS. Three fungal strains were selected as experimental strains, and the antifungal activity was tested in vitro according to the standardized antifungal sensitivity test method recommended by National Committee for Clinical Laboratory Standards (NCCLS). Results Compound B11 showed better activity against candida albicans SC5314 than fluconazole and was comparable to posaconazole; Compounds B10, B11 and B4 showed better activity against cryptococcus neoformanis H99 than fluconazole, while compounds B2, B3, B5, B6 and B7 showed similar activity to fluconazole against cryptococcus neoformanis H99; while all compounds showed poor activity against aspergillus fumigatus. Conclusion Some of the target compounds with n-propyl side chain and disubstituted benzyl group structure had certain antifungal activity and could be identified as potential lead antifungal drugs.

Microbial transformation of artemisinin and its derivatives / 中国中药杂志

Microbial transformation is an efficient enzymatic approach for the structural modification of exogenous compounds to obtain derivatives. Compared with traditional chemical synthesis, the microbial transformation has in fact the undoubtable advantages of strong region-and stereo-selectivity, and a low environmental and economic impact on the production process, which can achieve the reactions challenging to chemical synthesis. Because microbes are equipped with a broad-spectrum of enzymes and therefore can metabolize various substrates, they are not only a significant route for obtaining novel active derivatives, but also an effective tool for mimicking mammal metabolism in vitro. Artemisinin, a sesquiterpene with a peroxy-bridged structure serving as the main active functional group, is a famous antimalarial agent discovered from Artemisia annua L. Some sesquiterpenoids, such as dihydroartemisinin, artemether, and arteether, have been developed on the basis of artemisinin, which have been successfully marketed and become the first-line antimalarial drugs recommended by WHO. As revealed by pharmacological studies, artemisinin and its derivatives have exhibited extensive biological activities, including antimalarial, antitumor, antiviral, anti-inflammatory, and immunomodulatory. As an efficient approach for structural modification, microbial transformation of artemisinin and its derivatives is an increasingly popular strategy that attracts considerable attention recently, and numerous novel derivatives have been discovered. Herein, this paper reviewed the microbial transformation of artemisinin and its artemisinin, including microbial strains, culture conditions, product isolation and yield, and biological activities, and summarized the advances in microbial transformation in obtaining active derivatives of artemisinin and the simulation of in vivo metabolism of drugs.

Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives / 中国中药杂志

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.