A Highly Chemically Robust 3D Interpenetrated MOF Heterogeneous Catalyst for the Synthesis of Hantzsch 1,4-Dihydropyridines and Drug Molecules.

Metal-organic frameworks (MOFs) have attracted immense attention as efficient heterogeneous catalysts over other solid catalysts, however, their chemical environment instability often limits their catalytic potential. Herein, utilizing a flexible unexplored tetra-acid ligand and employing the mixed ligand approach, a 3D interpenetrated robust framework is strategically developed, IITKGP-51 (IITKGP stands for Indian Institute of Technology Kharagpur), which retained its crystallinity over a wide range of pH solution (4-12). Having ample open metal sites (OMSs), IITKGP-51 is explored as a heterogeneous catalyst in one-pot Hantzsch condensation reaction, with low catalyst loading for a broad range of substrates. The synthesis of drug molecules remains one of the most significant and emergent areas of organic and medicinal chemistry. Considering such practical utility, biologically important Nemadipine B and Nifedipine drug molecules (calcium channel protein inhibitor) are synthesized for the first time by using this catalyst and fully characterized via SC-XRD and other spectroscopic methods. This report inaugurates the usage of a MOF material as a catalyst for the synthesis of drug molecules.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.

Sensitive and effective method with 96-well plate for determination of levamlodipine in human plasma using LC-MS/MS.

we developed an effective protein precipitation method for determination of levamlodipine in human plasma using LC-MS/MS. Sample extraction was carried out by using liquid-liquid extraction in 96-well plate format. (S)-Amlodipine-d4 was used as internal standard (IS). The chromatographic separation was achieved using Philomen Chiral MX (2) column (3 µm, 2.1 × 100 mm). Mobile phase A was comprised of Acetonitrile (ACN), Mono ethanol amine (MEA) and Iso-Propyl alcohol (IPA) (1000:1:10, v/v/v), Mobile phase B was IPA-ACN (2:1, v/v). The flow rate was 0.4 mL/min. The total run time of each sample was 4.0 min with gradient elution. LC-MS/MS spectra were generated in positive ion mode, and multiple reaction monitoring (MRM) was used to detect the following transitions: m/z 409.20 â†’ 238.15 for levamlodipine and 415.25 â†’ 240.20 for (S)-Amlodipine-d4 (the IS). The method was linear from 50 to 10000 pg/mL（R2＝0.9988489）,and the lower limit of quantification (LLOQ) was 50 pg/mL. This method was applied to a bioequivalence study of levamlodipine.

The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Effect of Benidipine Alone and in Combination With Bosentan and Sildenafil in Amelioration of Pulmonary Arterial Hypertension in Experimental Model in Rats.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a persistent condition affecting the pulmonary arteries' endothelium. Benidipine, a calcium channel blocker, possesses vasodilatory, anti-inflammatory activity, reduces oxidative stress, and inhibits the activity of Transforming growth factor-ß (TGF-ß) and α-smooth muscle actin (α-SMA). The present study was designed to investigate the effect of benidipine alone and in combination with bosentan and sildenafil on monocrotaline (MCT)-induced pulmonary hypertension in a rat model. PAH was induced by a single-dose administration of MCT in rats. Animals were randomized into different groups and treated with benidipine alone and in combination with bosentan or sildenafil. Various parameters such as hemodynamic parameters, Fulton's index and oxidative stress parameters were performed. Additionally, histopathology of lung and right ventricular of heart tissue, immunohistochemistry, expression of α-SMA, endothelial nitric oxide synthase (eNOS), TGF-ß, and RT-PCR, and an in vitro study using human umbilical vein endothelial cells (HUVECs) was also carried out. Treatment of benidipine and its combination exhibited better prevention in the elevated right ventricular systolic pressure, right ventricular hypertrophy, rise in oxidative stress, and increase in expression of α-SMA and TGF-ß receptor 1 compared with MCT control group rats. In HUVECs, the expression of α-SMA was increased, whereas that of eNOS decreased after TGF-ß exposure and was substantially reversed after pretreatment with benidipine. We concluded that benidipine and its combination with bosentan and sildenafil exhibit beneficial effects in MCT-induced PAH through the eNOS/TGF-ß/α-SMA signaling pathway.

1,4-Dihydropyridine-based FA1 site-specific fluorescent probes for the selective detection and quantification of HSA levels in biofluids.

Human serum albumin (HSA) is a multifunctional circulatory protein essential for many physiological processes including oncotic pressure maintenance, ligand/drug binding and transport, antioxidant activity, etc. Abnormal HSA levels in biological fluids have been reported in a variety of clinical disorders, making it a potential biomarker for early diagnosis. Low serum albumin levels have been linked to increased long- and short-term mortality rates in ICU patients. Therefore, quantifying HSA in biofluids such as serum and urine offers a convenient approach for the early identification of underlying clinical conditions and assessing the risk factors. Herein, we report a series of fluorescent 1,4-dihydropyridine (DHP) derivatives for the detection and quantification of HSA in biofluids. Their response towards HSA can be tuned by varying the substituents at the C-4 and the N-1 of the DHP ring. Depending on the nature of the substituents, they generated either a turn-on or ratiometric response with a LoD in low nanomolar or subnanomolar levels. A pair of enantiomers obtained by introducing a chiral center on the N-substituents highlighted the importance of stereochemistry in HSA-ligand interactions. Quantification of HSA in complex biofluids, such as blood serum and urine, was also accomplished using these probes. The high selectivity of some of the probes towards HSA over the homologous BSA allowed the discrimination of these two proteins. The preferred binding location of the probes was the hemin binding site and the detection mechanism was identified as the restriction of intramolecular rotation. Additionally, a prototype of a smartphone-integrated point-of-care device was also fabricated to demonstrate the feasibility of utilizing these probes in clinical settings.

18F-Labeled dihydropyridines via Hantzsch reaction for positron emission tomography of P-glycoprotein dysfunction.

Despite the availability of various 11C-labeled positron emission tomography (PET) tracers for assessing P-glycoprotein (P-gp) function, there are still limitations related to complex metabolism, high lipophilicity, and low baseline uptake. This study aimed to address these issues by exploring a series of customized dihydropyridines (DHPs) with enhanced stability and reduced lipophilicity as alternative PET tracers for P-gp dysfunction. Compared with verapamil and the rest DHPs, dimethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1) exhibited superior cellular uptake differences between the human gastric cancer cell line SGC7901 and its drug-resistant counterpart. [18F]1 is successfully synthesized using a novel "hot-Hantzsch" approach in 22.1 ± 0.1 % radiochemical yields. MicroPET/CT imaging demonstrated that the uptake of [18F]1 in the brains of P-gp blocked mice increased by > 3 times compared to the control group. Additionally, [18F]1 displayed favorable lipophilicity (log D = 2.3) and excellent clearance characteristics, making it a promising tracer candidate with low background noise and high contrast.

Lercanidipine ameliorated doxorubicin-induced neuroinflammation and maintained the expressions of choline acetyltransferase via enhancing the levels of PI3K/AKT/HIF1-α expressions.

BACKGROUND: Doxorubicin (DOX) may cause various neurological side effects in the brain. Lercanidipine (LRD) has antioxidant, anti-inflammatory, and anti-apoptotic properties. The aim of this study was to investigate the potential benefits of. METHODS AND RESULTS: Lercanidipine in reducing doxorubicin-induced neuroinflammation and maintaining the expressions of choline acetyltransferase. Thirty-two adult Wistar albino female rats were divided into four groups as Control, DOX (20 mg/kg intraperitoneally), DOX + LRD 0.5 (0.5 mg/kg orally), and DOX + LRD2(2 mg/kg orally). Twenty-four hours after the last drug administration (9th day), brain tissues were taken for histopathological, immunohistochemical (choline acetyltransferase [CHAT], interleukin-10 [IL-10], and caspase-3 [Cas-3] staining), biochemical (total antioxidant status [TAS], total oxidant status [TOS], and oxidative stress index [OSI]), and genetic analyzes (PI3K/AKT/HIF1-α and IL-6 gene expressions). Histopathological analyses revealed hyperemia, slight hemorrhage, degeneration, neuronal loss, gliosis in the cerebellum, and neuronal loss in the brain cortex and hippocampus in the DOX group. According to other analyzes, decreased CHAT, PI3K, AKT, HIF1-α and increased IL-6, IL-10, Cas-3 expression were observed in the DOX group. CONCLUSIONS: Both LRD doses reversed all these findings, but LRD2 was observed to be more effective. In conclusion, we determined that LRD has potential therapeutic effect by reducing DOX-induced neuroinflammation, oxidative stress and apoptosis in brain tissues.

Penicimides A and B, two novel diels-alder [4 + 2] cycloaddition ergosteroids from Penicillium herquei.

Two novel naturally occurring [4 + 2] Diels-Alder cycloaddition ergosteroids (1 and 2), three undescribed oxidized ergosteroids (3-5), and eleven known analogs (6-16) were isolated from Penicillium herquei. Compounds 1 and 2 represent the first reported cycloadducts of a steroid with 1,4,6-trimethyl-1,6-dihydropyridine-2,5-dione or 4,6-dimethyl-1,6-dihydropyridine-2,5-dione to date. Compound 3 is the C-15 epimer of (22E,24R)-9α,11ß-dihydroxyergosta-4,6,8(14),22-tetraen-3-one (14). The chemical structures of these compounds were elucidated through widespread spectroscopic analyses, mainly including HRESIMS and 1D and 2D NMR data, calculated 13C NMR-DP4+ analysis, and electronic circular dichroism (ECD) data analyses. Biological evaluations of Compounds 1-16 revealed that 3, 9-11, and 15 inhibited the production of NO in LPS-induced RAW264.7 cells with an IC50 value from 7.37 ± 0.69 to 38.9 ± 2.25 µM (the positive control dexamethasone IC50: 9.54 ± 0.71 µM). In addition, Compound 3 exhibited a potent inhibitory effect on the secretion of the proinflammatory cytokines TNF-α and IL-6, the transcription level of the proinflammatory macrophage markers TNF-α, and the expression of the iNOS protein.

Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor.

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology 1,2 . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y1, Y2, Y4 and Y5 receptors, with different affinity and selectivity 3 . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y1 receptor (Y1R) 4 . A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity 4 , tumour 1 and bone loss 5 . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability 6 . Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.

Lacidipine Inhibits NF-κB and Notch Pathways and Mitigates DSS-Induced Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited. METHODS: We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling. RESULTS: Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons. CONCLUSION: Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC.

Anti-atrial Fibrillatory and Cardiorenal Protective Effects of the Combination of Valsartan and Cilnidipine in Dahl Salt-Sensitive Rats.

The current study aimed to investigate the anti-atrial fibrillatory (AF) effects of a combination of valsartan and a calcium channel blocker (cilnidipine or amlodipine) in Dahl salt-sensitive (Dahl S) rats. Seven-week-old male Dahl S rats were fed an 8% salt diet. Six weeks later, valsartan (60 mg/kg, Val group), cilnidipine + valsartan (10 + 60 mg/kg, CV group), amlodipine + valsartan (3 + 60 mg/kg, AV group), or vehicle was orally administered daily for 5 weeks. Echocardiography and atrial electrophysiological evaluations were performed on the last day of treatment. Blood pressure in each drug treatment group was lower than in the Vehicle group. The duration of AF induced by atrial burst stimulation was shorter in the Val group (3.2 ± 1.6 s) than in the Vehicle group (11.2 ± 6.0 s), which was further shortened in the CV and AV groups (1.1 ± 0.3 and 1.3 ± 0.3 s, respectively). Left ventricular ejection fraction and left ventricular fractional shortening were greater in the CV and AV groups than those in the Vehicle group. Urinary albumin excretion in the CV group was the lowest among the drug-treated groups. The results collectively suggest that the combination of a calcium channel blocker with valsartan could be useful in terms of its anti-AF action as well as for improving cardiac and renal functions.

Azelnidipine protects HL-1 cardiomyocytes from hypoxia/reoxygenation injury by enhancement of NO production independently of effects on gene expression.

It remains to be elucidated whether Ca2+ antagonists induce pharmacological preconditioning to protect the heart against ischemia/reperfusion injury. The aim of this study was to determine whether and how pretreatment with a Ca2+ antagonist, azelnidipine, could protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury in vitro. Using HL-1 cardiomyocytes, we studied effects of azelnidipine on NO synthase (NOS) expression, NO production, cell death and apoptosis during H/R. Action potential durations (APDs) were determined by the whole-cell patch-clamp technique. Azelnidipine enhanced endothelial NOS phosphorylation and NO production in HL-1 cells under normoxia, which was abolished by a heat shock protein 90 inhibitor, geldanamycin, and an antioxidant, N-acetylcysteine. Pretreatment with azelnidipine reduced cell death and shortened APDs during H/R. These effects of azelnidipine were diminished by a NOS inhibitor, L-NAME, but were influenced by neither a T-type Ca2+ channel inhibitor, NiCl2, nor a N-type Ca2+ channel inhibitor, ω-conotoxin. The azelnidipine-induced reduction in cell death was not significantly enhanced by either additional azelnidipine treatment during H/R or increasing extracellular Ca2+ concentrations. RNA sequence (RNA-seq) data indicated that azelnidipine-induced attenuation of cell death, which depended on enhanced NO production, did not involve any significant modifications of gene expression responsible for the NO/cGMP/PKG pathway. We conclude that pretreatment with azelnidipine protects HL-1 cardiomyocytes against H/R injury via NO-dependent APD shortening and L-type Ca2+ channel blockade independently of effects on gene expression.

New Dihydropyridine Derivative Attenuates NF-κB Activation via Suppression of Calcium Influx in a Mouse BV-2 Microglial Cell Line.

Activated microglia contribute to many neuroinflammatory diseases in the central nervous system. In this study, we attempted to identify an anti-inflammatory compound that could suppress microglial activation. We performed high-throughput screening with a chemical library developed at our institute. We performed a luciferase assay of nuclear factor-kappa B (NF-κB) reporter stable HT22 cells and identified a compound that was confirmed to inhibit the anti-inflammatory response in BV2 microglial cells. The selected dihydropyridine derivative can suppress the expression response of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF), as well as NF-κB phosphorylation and nuclear translocation, and reduce the intracellular calcium level. Thus, our identified compound has a potential role in suppressing microglial activation and may contribute to the development of a new therapeutic molecule against neuroinflammatory diseases.

Selective detection of azelnidipine in pharmaceuticals via carbon dot mediated spectrofluorimetric method: A green approach.

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N-doped CDs (N-CDs) were synthesized through a single-step hydrothermal process, using citric acid and urea as precursor materials. The prepared N-CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N-CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV-vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N-CDs and AZEL, leading to fluorescence quenching of N-CDs as a result of ground-state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10-200 µg/ml (R2 = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL.

Design, Synthesis and In-Silico Studies of Piperidine-Dihydropyridine Hybrids as Anticancer Agents.

In this study, we designed, synthesized and characterized a novel series of piperidine-dihydropyridine hybrid compounds and characterized them by 1H-NMR, 13C NMR, mass spectrometry (MS), and elemental analysis. Subsequently, we assessed their in vitro anticancer potentials against the human breast adenocarcinoma cell line MCF-7 and the lung cancer cell line A-549. Several of these compounds demonstrated significant activity, with IC50 values ranging from 15.94 µM to 48.04 µM for A-549 and 24.68 µM to 59.12 µM for MCF-7, when compared to the reference drug Cisplatin.Notably, a compound featuring a 3-fluoro substitution in the carboxamide series exhibited robust inhibitory effects, with an IC50 of 15.94±0.201 µM against A-549 cells and an IC50 of 22.12±0.213 µM against MCF-7 cells, respectively. Additionally, a compound containing a cyclobutyl ring displayed potent activity, with an IC50 of 16.56±0.125 µM against A-549 and an IC50 of 24.68±0.217 µM against MCF-7 cells, respectively. Furthermore, molecular docking studies against the Epidermal Growth Factor Receptor (EGFR) (PDB ID: 2J6M) revealed favourable binding scores and interactions, suggesting their potential as promising candidates for further investigation in the context of anticancer drug development.

Long term integrated biomarker responses in freshwater African catfish Clarias gariepinus exposed to a new brand of herbicide fluazifop-p-butyl.

The study investigated the sublethal effects of Fluazifop-p-butyl (FPB) on the haematological, biochemical and oxidative stress changes in Clarias gariepinus. Juvenile C. gariepinus were exposed to FPB concentrations of 1.80, 3.50, and 7.10 mg/l corresponding to 5, 10 and 20% of 96 h LC50 value of FPB respectively for 21 days and allowed to recover for 7 days. The blood, liver and gills were removed and analyzed. Fish exposed to different concentrations of FPB showed significant decline in the values the pack cell volume, hemoglobin and red blood cells but the white blood cell values increased. The neutrophil values increased while the lymphocyte declined but the monocytes, basophil and eosinophil values remain unchanged. The liver and gill aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase significantly increased compared to the control. There were mixed trends in the values of glucose but total protein was reduced in both tissues of the fish. There was significant decline in superoxide dismutase, catalase and glutathione peroxidase while malondialdehyde, total glutathione, and glutathione reductase increased in both liver and gill of the exposed fish. Following the 7-day withdrawal, most of the observed parameters returned to normal values. The present study revealed that FPB is toxic to C. gariepinus juveniles and prolonged exposure could result to major health risks to aquatic organisms, hence, they should be carefully used.

Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact.

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through ß-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1-filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.

Facile One-Pot Synthesis and Anti-Microbial Activity of Novel 1,4-Dihydropyridine Derivatives in Aqueous Micellar Solution under Microwave Irradiation.

The current study describes a novel and eco-conscious method to synthesize 1,4-dihydropyridine derivatives utilizing an aqueous micellar solution containing aluminum dodecyl sulfate, Al(DS)3, using readily available starting material. The final products were synthesized with excellent yields within remarkably quick reaction durations, promoting remarkable atom economy and minimizing environmental impacts. The present protocol has several advantages over other methodologies in terms of high yield (up to 97%) with excellent purity. Further, the synthesized 1,4-DHPs exhibit favorable to excellent resistance against examined bacterial and fungal species. Intriguingly, polar groups on the phenyl ring (5b, 5c, 5i and 5j) make the 1,4-DHPs equally potent against the microbes as compared to the standard drugs.

Establishing the Thermodynamic Cards of Dipine Models' Oxidative Metabolism on 21 Potential Elementary Steps.

Dipines are a type of important antihypertensive drug as L-calcium channel blockers, whose core skeleton is the 1,4-dihydropyridine structure. Since the dihydropyridine ring is a key structural factor for biological activity, the thermodynamics of the aromatization dihydropyridine ring is a significant feature parameter for understanding the mechanism and pathways of dipine metabolism in vivo. Herein, 4-substituted-phenyl-2,6-dimethyl-3,5-diethyl-formate-1,4-dihydropyridines are refined as the structurally closest dipine models to investigate the thermodynamic potential of dipine oxidative metabolism. In this work, the thermodynamic cards of dipine models' aromatization on 21 potential elementary steps in acetonitrile have been established. Based on the thermodynamic cards, the thermodynamic properties of dipine models and related intermediates acting as electrons, hydrides, hydrogen atoms, protons, and two hydrogen ions (atoms) donors are discussed. Moreover, the thermodynamic cards are applied to evaluate the redox properties, and judge or reveal the possible oxidative mechanism of dipine models.