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α3β4 Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α3β4 nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2, for the development of an α3β4 nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p-hydroxyl motif for ligand-receptor binding affinity. Four (R)- and (S)-quinuclidine-triazole (AK1-AK4) were synthesized and the binding affinity, together with selectivity to α3β4 nAChR subtype, were determined by competitive radioligand binding assay using [3H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α3β4 nAChR with a Ki value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α3β4 nAChR in comparison to α7 nAChR. The α3β4 nAChR selectivity of AK3 was considerably higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 was shown to be a promising α3β4 nAChR tracer for further development as a radiotracer for drug addiction.

Quetiapine fumarate is an atypical antipsychotic drug, which is clinically used for the treatment of depression and bipolar disorders. A stability indicating method is required for the quality control of pharmaceutical dosage forms. This work focused on the developments of a rapid stability indicating reversed-phase HPLC-UV method for determination of quetiapine fumarate in tablets and extemporaneous formulations. Quetiapine fumarate was simultaneously determined in the presence of three impurities: quetiapine related compound B, quetiapine related compound G, and quetiapine N-oxide within 9 min. Optimal HPLC conditions were realized using Zorbax C8 column (100 mm × 4.6 cm i.d., 3 μm particle). Gradient elution utilized mobile composition of 0.15% triethylamine (pH 6.0) and acetonitrile : methanol (80:20) mixture at a flow rate of 1.2 mL/min with detection wavelength at 252 nm. The proposed method showed good linearity (r2 > 0.998), precision (RSDs ≤ 2.2), and accuracy (%recovery 96.8 – 99.4, RSD ≤ 1.9) with acceptable limits of detection (LOD ≤ 3.0 μg/mL) and quantitation (LOQ ≤ 10 μg/mL) at RSD ≤ 2.8). The method was successfully applied to the determination of quetiapine fumarate in pharmaceutical formulations and stability testing of extemporaneous formulations.

Insulin fibril formation decreases the effectiveness of insulin therapy and causes amyloidosis in diabetes. Studies suggest that phytochemicals are capable of inhibiting fibril formation. Herein, we investigated the inhibitory effects of anthocyanins, including cyanidin, cyanidin-3-glucoside (C3G), cyanidin-3-rutinoside (C3R), malvidin, and malvidin-3-glucoside (M3G) on fibril formation. Our results revealed that anthocyanins (50-200 μM) significantly reduced the formation of insulin fibrils by increasing lag times and decreasing ThT fluorescence at the plateau phase. These findings were confirmed by TEM images, which showed reduced fibril length and number. Furthermore, FTIR analysis indicated that anthocyanins reduced the secondary structure transition of insulin from α-helix to β-sheet. Anthocyanins interacted with monomeric insulin (residues B8-B30) via H-bonds, van der Waals, and hydrophobic interactions, covering the fibril-prone segments of insulin (residues B12-B17). Based on the structure-activity analysis, the presence of glycosides and hydroxyl groups on phenyl rings increased intermolecular interaction, mediating the inhibitory effect of anthocyanins on fibril formation in the order of malvidin cyanidin M3G C3G C3R. Moreover, anthocyanins formed H-bonds with preformed insulin fibrils, except for malvidin. In preadipocytes, C3R, C3G, and cyanidin attenuated insulin fibril-induced cytotoxicity. In conclusion, anthocyanins are effective inhibitors of insulin fibril formation and cytotoxicity.

The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes &alpha, 3&beta, 4 and &alpha, 7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary &beta, 4-subunit of the &alpha, 4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the &alpha, 4 selectivity of the quinuclidine-triazole chemotype, explaining the 47&ndash, 327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the &alpha, 7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

An actinomycete strain CSR-4 was isolated from the rhizosphere soil of Zingiber montanum. Taxonomic characterization revealed strain CSR-4 was a member of the genus Microbispora. Whole-genome sequence analysis exhibited the highest average nucleotide identity (ANI) value (95.34%) and digital DNA–DNA hybridization (DDH) value (74.7%) between strain CSR-4 and the closest relative M. hainanensis DSM 45428T, which was in line with the assignment to same species. In addition, a new diterpene compound, 2α-hydroxy-8(14), 15-pimaradien-17, 18-dioic acid, and nine known compounds were isolated from the ethyl acetate crude extract of fermentation broth. Interestingly, a new diterpene displayed the suppressive effect on the recombinant human acetylcholinesterase (rhAChE) enzymes (IC50 96.87 ± 2.31 μg/ml). In silico studies based on molecular docking and molecular dynamics (MD) simulations were performed to predict a binding mode of the new compound into the binding pocket of the rhAChE enzyme and revealed that some amino acids in the peripheral anions site (PAS), anionic subsite, oxyanion site and catalytic active site (CAS) of the rhAChE have interacted with the compound. Therefore, our new compound could be proposed as a potential active human AChE inhibitor. Moreover, the new compound can protect significantly the neuron cells (% neuron viability = 88.56 ± 5.19%) from oxidative stress induced by serum deprivation method at 1 ng/ml without both neurotoxicities on murine P19-derived neuron cells and cytotoxicity against Vero cells.

A marine actinomycete strain C1-2 was taxonomically characterized as the genus Streptomyces , based on whole-genome sequence analysis. The highest average nucleotide identity (ANI) value (98.96%) and digital DNA–DNA hybridization (DDH) value (90.4%) were observed between Streptomyces sp. C1-2 and Streptomyces griseoaurantiacus. Thus, Streptomyces sp. C1-2 could be identified as S. griseoaurantiacus. Genome analysis revealed that Streptomyces sp. C1-2 contained 22 biosynthetic gene clusters (BGCs) for secondary metabolites , where among them, 54% have low similarities with known BGCs. The chemical investigation led to the isolation of three new manumycin-type derivatives and two known analog antibiotics named SW-B and cornifronin B. All compounds showed antioxidant activity with the half-maximal inhibitory concentration (IC 50 ) values in a range of 50.82 ± 0.8–112.04 ± 1.0 μg/mL with no cytotoxicity against Vero cells. This is the first report of the antioxidant property of manumycin-type derivatives. Moreover, two known compounds exhibited antifungal activity against Phytophthora capsici , Fusarium oxysporum f. sp. cucumerinum, and Magnaporthe grisea , with the minimum inhibitory concentration (MIC) values in a range of 125–500 μg/mL.

Transient receptor potential vanilloid 1 (TRPV1) activation by capsaicin binding increased intracellular calcium influx and stimulated adipocyte-to-adipocyte communication, leading to lipolysis. Generally, enhancement of π-stacking capabilities improves certain binding interactions. Notably, nitroarenes exhibit strong binding interactions with aromatic amino acid side chains in proteins. New capsaicinoid analogs were designed by substitution of the OCH3 group with a nitrogen dioxide (NO2) group on the vanillyl ring to investigate how π-stacking interactions in capsaicinoid analogs contribute to lipolysis. Capsaicinoid analogs, nitro capsaicin (5), and nitro dihydrocapsaicin (6) were prepared in moderate yields via coupling of a nitroaromatic amine salt and fatty acids. Oil Red O staining and triglyceride assays with 10 µM loading of capsaicin (CAP), dihydrocapsaicin (DHC), 5, and 6 were performed to investigate their effect on lipolysis in 3T3-L1 adipocytes. Both assay results indicated that 5 and 6 decreased lipid accumulation by 13.6% and 14.7%, respectively, and significantly reduced triglyceride content by 26.9% and 28.4%, respectively, in comparison with the control experiment. Furthermore, the decrease in triglyceride content observed in response to nitroarene capsaicinoid analogs was approximately 2-folds higher than that of CAP and DHC. These results arose from the NO2 group augmented π-π stacking with Tyr511 and the attractive charge interaction with Glu570 affecting binding interactions with TRPV1 receptors.