Withania somnifera, commonly known as Ashwagandha, is widely utilized for treating neurological disorders in both traditional and modern medicine. While its neuroprotective effects are linked to several bioactive compoun...Withania somnifera, commonly known as Ashwagandha, is widely utilized for treating neurological disorders in both traditional and modern medicine. While its neuroprotective effects are linked to several bioactive compounds, the individual safety profiles and potential cytotoxic effects of these compounds remain poorly understood. Previous studies from our research group have identified Withanone and Withanolide-A as neuroprotective agents. This study specifically evaluated the neurotoxic potential of Withaferin-A (WFA), a key steroidal lactone found in Withania somnifera, on differentiated SH-SY5Y cells. For six days, the SH-SY5Y cells were differentiated using 10 µM retinoic acid (RA). The neuronal phenotype was confirmed through morphological changes and increased expression of NeuN. Cytotoxicity assays demonstrated that WFA induces potent, dose-dependent cytotoxicity, resulting in approximately 50 %, 80 %, and 90 % cell death at concentrations of 0.6 µM, 1.2 µM, and 2.4 µM, respectively (p < 0.001). Treatment with WFA at 1.2 µM significantly increased both intracellular and mitochondrial reactive oxygen species (ROS), as shown by fluorescence imaging (p < 0.001). The loss of mitochondrial membrane potential was confirmed by JC-1 staining, indicating mitochondrial dysfunction. Western blot analysis indicated a dose-dependent increase in pro-apoptotic proteins Bax and Bid (p < 0.05 at 1.2 µM), an elevated Bax/Bcl-2 ratio (p < 0.001 at 1.2 µM), and enhanced activation of caspase-3, caspase-9, and cleavage of PARP-1 (p < 0.001 at 1.2 µM), indicating activation of the intrinsic apoptotic pathway. Molecular docking analysis revealed a strong binding affinity between WFA and PARP-1 (-8.2 kcal/mol), involving key residues Gly863, Ser904, and Tyr907, thereby supporting its role in PARP-1-mediated apoptosis. The computational findings were consistent with experimental observations of increased PARP-1 cleavage. This study concludes that WFA induces ROS-mediated mitochondrial dysfunction and caspase-dependent apoptosis in neuron-like cells. Consequently, future research should focus on critically assessing the safety and mechanistic effects of individual bioactive constituents of Withania somnifera, despite the well-established therapeutic potential of the plant.
BACKGROUND: The pandemic of COVID-19 caused by the SARS-CoV-2 has irrevocably altered the lives of human beings and is challenging national health systems worldwide. Many treatment strategies have been put out to lessen...BACKGROUND: The pandemic of COVID-19 caused by the SARS-CoV-2 has irrevocably altered the lives of human beings and is challenging national health systems worldwide. Many treatment strategies have been put out to lessen the damage to the inflammatory organs in COVID-19 pneumonia cases, and corticosteroids are one of the most promising pharmaceutical treatments. AIM: To assess the efficacy and safety of various corticosteroids (Dexamethasone, Methylprednisolone, Prednisolone, and Hydrocortisone) among patients with moderate and severe COVID-19 who received corticosteroids during their hospital stay. METHODS: It was a record-based retrospective cohort study conducted between April 1st, 2020, and June 30th, 2021, at the tertiary care teaching hospital, All India Institutes of Medical Sciences (AIIMS), Raipur. Only patients who received corticosteroids during their hospital stay were included in the study. COVID-19 severity was assessed using the WHO ordinal scale, where scores range from 0 (uninfected) to 8 (death). RESULTS: Out of 431 patients, 243 (56 %) patients survived and 188 (44 %) patients did not survive. Most patients were admitted with a WHO ordinal score of 4 (n = 239, 55.4 %), followed by score 5 (n = 4, 1 %), who were discharged with a score of 0 or 1 and more in group 1. More patients died in group 5 and group 2. 155 (35.9 %) patients did not survive in the severe group, followed by 33 (7.7 %) in the moderate group. CONCLUSION: More research on the safety and effectiveness of corticosteroids is needed to improve the in-hospital care of COVID-19. The study found that using corticosteroids in combination and higher doses for longer durations will help policymakers recommend strict guidelines. We looked for dose and duration compliance and the relationship between adverse events and diabetes patients. However, the findings of this study support dexamethasone as a promising agent in the fight against SARS-CoV-2.
A series of six α-bromoketones derived from lithocholic acid was synthesized through an oxidative bromination reaction, with four of these compounds being reported for the first time. All products were characterized usin...A series of six α-bromoketones derived from lithocholic acid was synthesized through an oxidative bromination reaction, with four of these compounds being reported for the first time. All products were characterized using NMR, IR spectroscopy, and mass spectrometry. The structures and crystalline packing of two α-bromoketones were further confirmed through X-ray diffraction analysis. The antibacterial activity of the compounds was evaluated against both Gram-negative and Gram-positive bacterial strains of clinical relevance.
BACKGROUND: Due to the severe hypersensitivity risks associated with some xanthine oxidase (XO) inhibitors, there is a pressing need to develop novel agents with improved safety and effective ADME profiles. This study ev...BACKGROUND: Due to the severe hypersensitivity risks associated with some xanthine oxidase (XO) inhibitors, there is a pressing need to develop novel agents with improved safety and effective ADME profiles. This study evaluates the antihyperuricemic and antioxidant potential of Erigeron annuus Lin. (E. annuus) using in vitro and in silico models. OBJECTIVE: To assess the in vitro XO inhibitory and antioxidant activities of the hydroalcoholic crude extract, fractions, and isolated compounds from the aerial parts of E. annuus Lin. METHODS: A hydroalcoholic extract was prepared using a Soxhlet apparatus. Column chromatography and spectroscopic techniques were employed to isolate and identify two phytosterols: RR1 (β-sitosterol) and RR2 (stigmasterol). A further pharmacophore-based hypothesis was developed using DE Shaw Desmond software; an in-silico profile was also evaluated using LeadIT software and Swiss ADME, respectively. XO inhibitory activity was measured using a Biotek multi-mode plate reader, and antioxidant activity was assessed via the DPPH and FRAP assay. Additionally, potent compound RR2 was also evaluated for its cytotoxicity against HepG2 cell line. RESULTS: All tested extracts and fractions inhibited XO activity, with IC values ranging from 0.086 µg/mL to 36.71 µg/mL. Allopurinol, used as a positive control, had an IC of 0.027 µg/mL. The hexane fraction of E. annuus exhibited the most vigorous XO inhibitory activity (IC = 0.086 µg/mL). RR2 (stigmasterol) showed notable inhibition from this fraction with an IC of 0.331 µg/mL. Antioxidant assays and cytoxicity study also supported the bioactivity of these fractions. CONCLUSION: The hexane fraction of E. annuus demonstrated potent XO inhibitory activity, highlighting its potential as a source for developing herbal treatments for hyperuricemia and gout. The study validates traditional use and supports the pharmacophore hypothesis, suggesting that structural optimization of the sterol nucleus could enhance therapeutic efficacy.
Cyp27b1 polymorphisms are stated to be associated with different diseases including tuberculosis (TB). Since the gene variants located in the promoter region may have a significant influence on gene transcription/transla...Cyp27b1 polymorphisms are stated to be associated with different diseases including tuberculosis (TB). Since the gene variants located in the promoter region may have a significant influence on gene transcription/translation and Cyp27b1 enzyme is involved in critical steps in vitamin D metabolism, we aim to study whether Cyp27b1 gene promoter variants namely -1077 (C/G), -1260 (C/A) and the region immediately 5' to the promoter -1918 (C/T) have any linkage with pulmonary tuberculosis risk/defence and to determine their influence on vitamin D level in normal healthy controls (HCs) and pulmonary tuberculosis (PTB) patients of the South Indian population. The polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method were used to genotype the genomic DNA after it was extracted using the salting-out approach. The Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure the amount of vitamin D. In the co-dominant model, a significant association was detected with TB liability in the -1077 "GG" genotype [Odds ratio (OR): 2.10(1.18-3.73); p = 0.015]. In addition, a noteworthy linkage was detected with TB protection in the dominant model [GG vs CG + CC, OR: 0.40(0.21-0.75); p = 0.0035]. In the -1918 (C/T) variant, a substantial linkage was detected in the heterozygous -1918 "CT" genotype with TB risk [OR: 1.90 (1.05-3.44); p = 0.046] in co-dominant model, whereas a protective linkage was detected in less recurrent "TT" genotype [OR: 0.42 (0.19-0.94); p = 0.049] with TB. Furthermore, those risky genotypes are substantially linked with more TB risk in males than females. Strong links between -1077 and -1260 variations were revealed by haplotype analysis, and its haplotypes "GC" (-1077G, -1260C) were found to be significantly associated with increased TB risk. Vitamin D deficiency (<20 ng/ml) was detected at a higher frequency in PTB patients than HCs in -1077 "GG", -1260 "CA" and -1918 "CT" risky genotypes. This needs to be confirmed by bigger sample sizes in future research.
PURPOSE: This study aimed to evaluate the potential impact of serum E2 levels on vaginal pH regulation and Candida colonization in women undergoing infertility treatment, emphasizing mucosal barrier dynamics and epitheli...PURPOSE: This study aimed to evaluate the potential impact of serum E2 levels on vaginal pH regulation and Candida colonization in women undergoing infertility treatment, emphasizing mucosal barrier dynamics and epithelial immune modulation. METHODS: In this prospective observational study, 60 women aged 20-49 undergoing long-protocol ovulation induction were enrolled. Serum E2 levels, vaginal pH, and fungal cultures were assessed on cycle day 2 (baseline) and again at the time of estradiol peak, which was typically within 24 h before human chorionic gonadotropin (hCG) administration and after ultrasound-confirmed follicular maturation. Pre- and post-treatment paired samples were statistically compared, with significance set at p < 0.05. RESULTS: Post-treatment analysis revealed a significant increase in serum E2 and vaginal pH levels (p < 0.05). However, no significant correlation was observed between E2 and vaginal pH, Candida colonization, or vulvovaginal symptoms. Likewise, vaginal pH was not a significant predictor of fungal growth. Notably, a significant association between baseline symptoms and culture positivity was observed pre-treatment, which was not present post-treatment. CONCLUSION: These findings indicate that the hormonal increase in E2 during infertility treatment, although associated with elevated vaginal pH, does not increase the risk of Candida infections. The preservation of epithelial barrier function despite hormonal shifts may explain this finding. These results support the microbiological safety of controlled ovarian stimulation protocols with regard to Candida susceptibility.
Concordia in Antarctica is one of the most remote and inhospitable inhabited places on the planet. Overwintering at Concordia presents extreme environmental conditions combining both physiological stress [three-month-lon...Concordia in Antarctica is one of the most remote and inhospitable inhabited places on the planet. Overwintering at Concordia presents extreme environmental conditions combining both physiological stress [three-month-long period of polar night (early May to early August) and three-month period of polar day (early November to early February), severe cold, and high-altitude hypoxia] and conditions of isolation and confinement known to induce both physical and cognitive alterations. However, given the very small number of subjects experiencing such conditions, literature remains scarce on the real impact of an overwintering period on steroid hormone changes. Using monthly records, we therefore assessed the impact of an overwintering in 23 male participants on awakening and evening concentrations of cortisol and testosterone, body composition and physical aptitude assessed using a Chester submaximal test. Across overwintering, 10 of the 23 subjects (Group 1) lost more than 2 % of their muscle mass. Awakening and evening concentrations of cortisol and testosterone were preserved throughout wintering with no significant deterioration in physical aptitude. However, Group 1 vs. Group 2 participants had higher end-exercise heart rate and lower testosterone fluctuations between awakening and evening (p < 0.05). These results highlighted the great adaptation of the hypothalamic-pituitary-adrenal and gonadal axis functions to long-term extreme polar exposure. Further studies are needed to determine the mechanisms underlying the alteration in muscle mass occurring in almost half of the winterers, taking into account the subjects' energy intake and expenditure as well as their initial physical aptitude, in order to propose effective diet and physical activity countermeasures.
The development and maturation of T cells requires an efficient cell volume regulation (CVR) system in which the volume-sensitive outwardly rectifying anion channel (VSOR/VRAC) plays a pivotal role. Ecdysterone (20-hydro...The development and maturation of T cells requires an efficient cell volume regulation (CVR) system in which the volume-sensitive outwardly rectifying anion channel (VSOR/VRAC) plays a pivotal role. Ecdysterone (20-hydroxyecdysone, 20HE) is known to exert multiple effects in mammals, but the response of the thymus and thymocytes to this hormone remains virtually unexplored. In the present study, we observed a bidirectional effect of 20HE on the thymus and its cellular contents. In the short term, thymocytes responded by blockage of the VSOR/VRAC with a half-maximal effective concentration of ∼33-37 μM and a maximum observed inhibition by 57-62 % at 100 μM. Suppression of the thymocytic RVD occurred to a less degree of ∼31 % but more efficiently with a half-maximal concentration at ∼8 μM. In contrast to the short-term effects, prolonged exposure of thymocytes to 20HE increased their proliferative activity under primary culture conditions (by ∼67 % after 24 h) without detectable change in the VSOR/VRAC activity. Consistent with this result, at the whole organism level, administration of 20HE per os for 5 days strongly stimulated thymic growth (by ∼61 %) and up-regulated the CVR efficiency of the cells isolated from the 20HE-treated animals (parameter RVD increase by ∼12 %). The results obtained suggest that systemic effects of 20HE, which become apparent only after long-term exposure in primary culture conditions or in the whole organism, may counteract the acute blockade of thymocyte VSOR/VRAC and RVD induced by the steroid in the buffered saline.
Prolonged flunitrazepam use has been reported to be increasing among young adolescents, and it has been reported to induce hyperprolactinemia, causing gross impairment of testicular function, ultimately resulting in male...Prolonged flunitrazepam use has been reported to be increasing among young adolescents, and it has been reported to induce hyperprolactinemia, causing gross impairment of testicular function, ultimately resulting in male infertility. Hence, this current study seeks to examine the possible protective potential of the micronutrient Vitamin D3 in mitigating flunitrazepam-induced testicular dysfunction. Adult male rats (Wistar strain), weighing 200-220 g, were categorized into four groups: Vehicle [0.3 ml of distilled water and 0.2 ml of olive oil, the respective solvents for flunitrazepam (Fluni) and Vitamin D3 (V.D3)], Fluni [0.35 mg/kg], V.D3 [0.01 mg/kg], and Fluni [0.35 mg/kg] + V.D3 [0.01 mg/kg]; these groups were treated orally for 56 days before the testes and epididymides were removed for biochemical and histological processing. Vitamin D3 supplementation significantly prevented hyperprolactinemia and sperm cell damage, reduced testicular lipid peroxidation, and significantly increased serum concentrations of reproductive hormones, testicular steroidogenic enzymes, antioxidants, and improved inflammatory markers. It also improved sperm energy utilization, quality, and transmembrane pump activities, with a marked recovery of the epididymal smooth muscles and testicular interstitial and spermatogonial cells in the flunitrazepam-treated rats. This present study shows that Vitamin D3 supplementation prevents impairment of testicular functions and ensures improved sperm function in flunitrazepam-exposed rats. Meanwhile, further molecular studies and clinical trials are encouraged to explore Vitamin D3's possible intervention in drug-induced male infertility, given the limitations of animal studies.
Picoa lefebvrei (Pat.) Maire is a truffle species that belongs to the Cistaceae family and grows mycorrhizally on the roots of Helianthemum species. Picoa species, which is indigenous to Western Anatolia and Tunisia, hav...Picoa lefebvrei (Pat.) Maire is a truffle species that belongs to the Cistaceae family and grows mycorrhizally on the roots of Helianthemum species. Picoa species, which is indigenous to Western Anatolia and Tunisia, have been preferred as food and have economic potential. Recently, interest in bioactive compounds of mushrooms has increased and it is known that edible mushrooms and some truffles are used in the new generation of biotherapeutics. In this report, eight compounds were isolated from P. lefebvrei extracts namely, brassicasterol (1), brassicasteryl-β-ᴅ-glucopyranoside (2), uracil (3), l-uridine (4), erythritol (5), α-ᴅ-glucopyranosyl-α-ᴅ-glucopyranoside (6), brassicasteryl linoleate (7) and 5α-6α-epoxy ergosta-7,22-diene-3β-ol (8) via various chromatographic methods. Also, antioxidant, anticholinesterase, anti-urease, and cytotoxic (against MCF-7, H1299 and L929 cell lines) activities of extracts and compounds from P. lefebvrei were investigated. Compound 4 exhibited the highest antioxidant activity with IC values of 92.61 ± 0.10, 70.55 ± 0.84 and 112.08 ± 0.15 µg/mL in the DPPH (2,2-Diphenyl-1-picrylhydrazyl), ABTS (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and CUPRAC (Cupric Ion Reducing Antioxidant Capacity) assays, respectively. Compounds 3 and 8 exhibited the highest activities against acetylcholinesterase (AChE) (44.59 ± 0.37 % and 40.26 ± 0.53 %) and butyrylcholinesterase (BChE) (53.15 ± 1.07 % and 54.97 ± 0.41 %). Compound 8 had strongest cytotoxicity with IC value of 33.94 ± 0.47 µg/mL against the H1299 lung cancer cells. Nevertheless, compound 1 (IC:24.72 ± 0.75 µg/mL), showed the greatest cytotoxicity against the MCF-7 breast cancer cells. These findings indicate that P. lefebvrei, is rich in steroidal compounds and is a possible source of ergostane-type steroids. Furthermore, this first detailed investigation highlights the potential of P. lefebvrei as a natural food and as a source of bioactive compounds.
Certain mushrooms are used as low-calorie food supplements due to their excellent taste, and presence of a variety of essential vitamins, minerals and secondary metabolites. Some of them have therapeutic significance, an...Certain mushrooms are used as low-calorie food supplements due to their excellent taste, and presence of a variety of essential vitamins, minerals and secondary metabolites. Some of them have therapeutic significance, and used in traditional medicines. Mushrooms cells can also be used as biocatalysts for the derivatization of organic compounds. During the current study, 3β-hydroxy-24-methylenelanost-8-en-21-oic acid (1) was isolated from Laetiporus sulphureus (Bull.) Murrill. The cell culture of the same mushroom was used for the biotransformation of breast cancer drug, exemestane (2) into a new analogue, 18-hydroxy-6-methylene-androsta-1,4-diene-3,17-dione (3). Compounds 1, and 3 were purified by using various chromatographic techniques, and their structures were determined with the help of 1D- and 2D-NMR, HREI-MS, and IR spectroscopic techniques. Since compound 1 also has a steroidal skeleton (like aromatase inhibiting drug exemestane (2)), the metabolite 1 was also evaluated for its aromatase inhibitory potential, along with a new transformed product 3. Aromatase plays a crucial role in estrogen biosynthesis, and therefore its inhibition is a key approach for the treatment of estrogen receptor-positive (ER+) breast cancers. Compounds 1 and 3 demonstrated a significant aromatase inhibition, with IC values of 590 ± 0.03 nM and 337.5 ± 0.01 nM, respectively, relative to exemestane's IC of 210.0 ± 0.16 nM. Furthermore, in silico studies predicted that these inhibitors 1-3 were able to occupy the active site and interacted with catalytically important residues of the enzyme. While molecular dynamic simulation predicted the stability of aromatase- ligand complexes. The studies identified that metabolites 1 and 3 can serve as drug candidate after further development.
25-Hydroxycholesterol not only exhibits various important biological activities but also plays a crucial role in the synthesis of 25-hydroxyvitamin D. To date, researchers have proposed multiple synthetic routes for 25-h...25-Hydroxycholesterol not only exhibits various important biological activities but also plays a crucial role in the synthesis of 25-hydroxyvitamin D. To date, researchers have proposed multiple synthetic routes for 25-hydroxycholesterol. Herein, a novel synthetic method for 25-hydroxycholesterol is described, involving a seven-step reaction that starts from economical and commercially available plant-derived bisnoralcohol, with an overall yield of up to 43.4%. Key reaction conditions, including solvents, reaction temperatures, bases and catalysts, were thoroughly investigated and optimized. This novel synthetic route provides a cost-effective strategy for the potential large-scale production of plant-derived 25-hydroxycholesterol.
BACKGROUND: Etomidate, a general anaesthetic, is known to possess inhibitory activity on steroid 11β-hydroxylase at subanaesthetic concentrations. An emerging trend of abuse of etomidate as well as its analogues propoxat...BACKGROUND: Etomidate, a general anaesthetic, is known to possess inhibitory activity on steroid 11β-hydroxylase at subanaesthetic concentrations. An emerging trend of abuse of etomidate as well as its analogues propoxate/isopropoxate has recently been observed. Their effects on adrenal steroidogenesis as drugs of abuse remain to be elucidated. Steroid excretion patterns of etomidate and propoxate/isopropoxate users were analysed for evidence of disrupted steroidogenesis. METHOD: This is a retrospective, cross-sectional study. Urine steroid profiling by gas chromatography-mass spectrometry-based method was performed on spot urine specimens positive for etomidate, propoxate/isopropoxate and/or their metabolites by liquid chromatography-tandem mass spectrometry. Results were compared with routine clinical specimens with normal adult (≥ 18 years of age) urine steroid profiles, analysed between 1st January 2022 and 24th June 2024. Additional clinical and biochemical data were retrieved from the electronic patient records for review. RESULTS: Ten male and ten female adult users, aged 18 to 54 years, were included in this study. Their steroid excretion patterns were compared against 377 normal profiles. Hypokalaemia and concomitant drugs of abuse were present in the majority of cases. Psychiatric symptoms were noted in eight out of 20 cases. Multiple metabolites, including tetrahydro-11-deoxycortisol, tetrahydro-deoxycorticosterone and multiple adrenal androgen metabolites, were elevated in etomidate and propoxate/isopropoxate abusers. The pattern indicates 11β-hydroxylase inhibition. CONCLUSION: 11β-hydroxylase inhibition was demonstrated in recreational users of etomidate and/or its analogues, explaining the clinical features of hypokalaemia, and hyperandrogenism in female patients. Misuse of the compounds could be a harbinger of an increasing prevalence of acquired 11β-hydroxylase deficiency.
PURPOSE: Daidzein, a soy-derived phytoestrogen, administered directly in the heart does not show cardioprotective effects against myocardial ischemia-reperfusion (IR) in isolated rat hearts. This study aimed to investiga...PURPOSE: Daidzein, a soy-derived phytoestrogen, administered directly in the heart does not show cardioprotective effects against myocardial ischemia-reperfusion (IR) in isolated rat hearts. This study aimed to investigate whether cardioprotective effects of enteral daidzein against myocardial IR are promoted by equol, a metabolite of daidzein, through phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. METHODS: Two experiments involving the Langendorff system were performed. During experiment 1, rats were divided into: daidzein group received 100 mg/kg of daidzein and control group received saline enterally 24 h before heart excision. After the rats were euthanized, blood samples were obtained to measure equol levels. Hearts were perfused with modified Krebs-Henseleit (KH) buffer before and after no-flow ischemia. During experiment 2, rats were divided into daidzein + WT (wortmannin) and control + WT groups, where daidzein (100 mg/kg) or saline (control + WT) was administered enterally 24 h before heart excision. To assess the role of the PI3K/Akt signaling pathway, an inhibitor of PI3K (wortmannin) was administered before and after no-flow ischemia in both groups. The primary outcome was the maximum left ventricular pressure derivative (LV dP/dt max) after reperfusion. RESULTS: LV dP/dt max values of the daidzein group at 10, 15, and 20 min after reperfusion were significantly higher than those of the control group (P < 0.05). This effect was diminished by wortmannin. Enteral daidzein significantly increased serum equol levels (daidzein group: 541.5 ± 330.8 nmol/L; control group: 140.6 ± 43.3 nmol/L; P = 0.0043). CONCLUSION: Enteral daidzein exhibited cardioprotective effects via PI3K/Akt signaling pathway activation, probably induced by increased serum equol level.
A series of new heterocyclic ursane and 28-norursane hybrids - derivatives of 5-amino-1,2,3,4-thiatriazole, 1-tetrazole-5-thione, and 1-tetrazole-5-amines were prepared. Reacting triterpenoids holding NCS groups at diffe...A series of new heterocyclic ursane and 28-norursane hybrids - derivatives of 5-amino-1,2,3,4-thiatriazole, 1-tetrazole-5-thione, and 1-tetrazole-5-amines were prepared. Reacting triterpenoids holding NCS groups at different distances from the pentacyclic backbone with hydrazine hydrate resulted in ursane-derived hydrazinecarbothioamides. Subsequent nitrosation afforded terpenoid derivatives of 5-amino-1,2,3,4-thiatriazole. Heterocyclization of amino-thioureas with 3β-acetoxyurs-12-en-28-yl substituent under the action of Hg(OAc)-NaN led to hybrids of 1-tetrazole-5-amines. 1-Tetrazole-5-thiones with different positions of heterocycle relative to the triterpene skeleton were prepared by coupling sodium azide with triterpene isothiocyanates. The activity of the new heterocyclic derivatives as inhibitors of 3CLpro of SARS-CoV-2 was investigated. Remarkable inhibition was observed for the 1-tetrazole-5-thione hybrids of triterpenoids. The highest activity among the studied compounds was provided by the combination of a 1-tetrazole-5-thione moiety at the C(28)H group of the ursane frame having a free OH group at the 3-position. Molecular docking assumed the covalent binding of 3CLpro via the formation of a disulfide bond between the thiol groups of the catalytic Cys145 and the tetrazole heterocycle of the new hybrid compounds. The triterpenoid backbone provided multiple external hydrophobic contacts essential for the stability of the complex. The results demonstrate the potential of heterocyclic thione hybrids as non-peptidomimetic covalent inhibitors targeting 3CLpro protease (3-Chymotrypsin-like Protease).
A new 18,22-cyclosterol, aspersteroline A (1), and a new DMOA-derived meroterpenoid, asperterpene O (2), along with three known compounds (3 - 5), namely mer-NF8054X (3), terretonin D (4), and asperterpene J (5), were is...A new 18,22-cyclosterol, aspersteroline A (1), and a new DMOA-derived meroterpenoid, asperterpene O (2), along with three known compounds (3 - 5), namely mer-NF8054X (3), terretonin D (4), and asperterpene J (5), were isolated from the soil-derived Aspergillus versicolor QC812. The structures of new compounds were established based on widespread spectrographic methods, mainly including 1D & 2D NMR and HRESIMS analyses, and the absolute configurations were further confirmed by comparison of calculated and experimental electronic circular dichroism (ECD) curves. The cytotoxicity of isolates was evaluated on five human tumor cell lines, 1 and 3 showed moderate cytotoxic activities against HL-60.
BACKGROUND: Sarcococca species (the family Buxaceae), containing a large number of steroidal alkaloids, were often used as medicinal plants for treating various ailments, such as fever, pain, and inflammation. OBJECTIVE:...BACKGROUND: Sarcococca species (the family Buxaceae), containing a large number of steroidal alkaloids, were often used as medicinal plants for treating various ailments, such as fever, pain, and inflammation. OBJECTIVE: The current study aims to highlight the natural observation and pharmacological actions of Sarcococca steroidal alkaloids and related compounds. METHODS: Scientific literature of phytochemical studies and pharmacological examinations of Sarcococca species were collected from four main sources: Google Scholar, Web of Science, PubMed, and journal websites. "Sarcococca" and "steroidal alkaloids" were the primary keywords to search for references. The study covers almost all English publications from the 1960 s to the present. ChemDraw Ultra 12.0 was used to draw chemical structures of phytochemicals. RESULTS: Phytochemical results indicated that about 170 secondary metabolites have been detected in Sarcococca, of which 144 compounds (84.7%) can be classified as steroidal alkaloids. Other classes included sterols, triterpenoids, flavonoids, and mono-phenols. Sarcococca crude plant extracts, fractions, and their steroidal alkaloid isolates have pharmacological properties, such as cytotoxic, antimicrobial, antioxidative, antiinflammatory, antileishmanial, antiplasmodial, and antidiabetic activities. They were also recorded to protect against harmful conditions to the neurons, liver, and gastrointestinal system, and exert vasorelaxant, analgesic, estrogen biosynthesis, and nematicidal activities. Some steroidal alkaloids are better than the standard drugs to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Generally, substituted groups at nitrogenous atoms might be attributed to the differences in pharmacological results. CONCLUSION: Advances in chromatographic isolations of steroidal alkaloids to obtain huge amounts are necessary. In vivo biological experiences and clinical testing are encouraged.