High transfection efficiency and low toxicity cationic lipids with aminoglycerol–diamine conjugate

The solid phase synthesis of a library of aminoglycerol–diamine conjugate-based transfection agents having urea linkage between diverse length of diamines and various lengths of hydrophobic tails is described. These compounds were characterized and structure–activity relationships were determined for DNA binding and transfection ability when formulated as cationic liposomes. Cationic lipids with short spacer length and short hydrophobic tails bound to DNA and delivered DNA into HEK293 cells more efficient than those with longer ones. Transfection efficiency of some of the cationic liposomes was superior to that of the commercial transfection agents, Effectene^TM_, DOTAP and DC-Chol. The lipids 6Ab and 6Bb did not require the helper lipid DOPE to produce high-efficiency transfection of human cells while displaying minimal cytotoxicity. This suggests that these newly described aminoglycerol-based lipids should be very promising in liposome-mediated gene delivery and illustrate the potential of solid phase synthesis method for non-viral vector discovery.     

C-peptide inhibitors of Ebola virus glycoprotein-mediated cell entry: Effects of conjugation to cholesterol and side chain–side chain crosslinking

We previously described potent inhibition of Ebola virus entry by a ‘C-peptide’ based on the GP2 C-heptad repeat region (CHR) targeted to endosomes (‘Tat-Ebo’). Here, we report the synthesis and evaluation of C-peptides conjugated to cholesterol, and Tat-Ebo analogs containing covalent side chain–side chain crosslinks to promote α-helical conformation. We found that the cholesterol-conjugated C-peptides were potent inhibitors of Ebola virus glycoprotein (GP)-mediated cell entry (～10³-fold reduction in infection at 40 μM). However, this mechanism of inhibition is somewhat non-specific because the cholesterol-conjugated peptides also inhibited cell entry mediated by vesicular stomatitis virus glycoprotein G. One side chain–side chain crosslinked peptide had moderately higher activity than the parent compound Tat-Ebo. Circular dichroism revealed that the cholesterol-conjugated peptides unexpectedly formed a strong α-helical conformation that was independent of concentration. Side chain–side chain crosslinking enhanced α-helical stability of the Tat-Ebo variants, but only at neutral pH. These result provide insight into mechanisms of C-peptide inhibiton of Ebola virus GP-mediated cell entry.     

Synthesis and biological evaluation of novel tris-chalcones as potent carbonic anhydrase,acetylcholinesterase, butyrylcholinesterase and α-glycosidase inhibitors

A novel class of fluoro-substituted tris-chalcones derivatives (5a-5i) was synthesized from phloroglucinol and corresponding benzaldehydes. A three step synthesis method was followed for the production of these tris-chalcone compounds. The structures of the newly synthesized compounds (5a-5i) were confirmed on the basis of IR, ¹H NMR, ¹³C NMR, and elemental analysis. The compounds’ inhibitory activities were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). These chalcone derivatives had K_i values in the range of 19.58–78.73 nM for hCA I, 12.23–41.70 nM for hCA II, 1.09–6.84 nM for AChE, 8.30–32.30 nM for BChE and 0.93 ± 0.20–18.53 ± 5.06 nM against α-glycosidase. These results strongly support the promising nature of the tris-chalcone scaffold as selective carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase inhibitor. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer’s disease; type-2 diabetes mellitus that are associated with high enzymatic activity of carbonic anhydrase, acetylcholine esterase, butyrylcholinesterase, and α-glycosidase.     

New phenolic glycosides isolated from Penthorum chinense Pursh

A phytochemical investigation from 80% ethanol extract of Penthorum chinense Pursh (Saxifragaceae) resulted in the isolation of three new phenolic glycosides (1–3), together with three known phenolic glycosides (4–6). The structures of the new compounds were deduced from their comprehensive spectroscopic analysis including IR, HR-EI-MS, ¹H NMR, ¹³C NMR, DEPT, COSY, HMBC and HMQC. And the structures of known compounds 4–6 were identified by comparison of their spectral data with those reported in the literature.     

Synthesis and in vitro biological evaluation of novel coumarin derivatives containing isoxazole moieties on melanin synthesis in B16 cells and inhibition on bacteria

A novel series of coumarin derivatives 6a–o, bearing isoxazole moieties were designed and synthesized. After that, they were evaluated for melanin synthesis in murine B16 cells and inhibitory effect on the growth of CA (Candida albicans), EC (Escherichia coli), SA (Staphylococcus aureus). It was found that eleven compounds (6b–f, 6j–o) showed a better activity on melanin synthesis than positive control (8-MOP). Among them, compounds 6d (242%) and 6f (390%), with nearly 1.6 and 2.6-fold potency compared with 8-MOP (149%) respectively, were recognized as the most promising candidate hits for further pharmacological study of anti-vitiligo.Seven halogen substituted compounds exhibited moderate antimicrobial activity against CA. It is interesting that 6e–f and 6l–m, which had two halogens on the benzene showed a comparable activity with Amphotericin B against CA.The evaluation of melanin synthesis in B16 cells and inhibitory effect on bacteria of above structurally diverse derivatives had also led to an outline of structure-activity relationship.     

Chemical constituents from the seeds of Raphanus sativus L. and their chemotaxonomic significance

The phytochemical investigations on the seeds of Raphanus sativus L. led to the isolation and identification of 15 compounds, including eleven sinapoyl derivatives (1–11), two terpenes (12–13), and two phenolic acids (14–15). All chemical structures were elucidated via ¹H NMR and ¹³C NMR spectroscopic methods, and further supported by comparison with literature data. Compound 11 was isolated from the genus Raphanus for the first time. Notably, Compounds 7, 9, and 12–14 were reported in the Brassicaceae family for the first time. The chemotaxonomic significance of these compounds is discussed.     

Synthesis,antiviral activity and molecular modeling of oxoquinoline derivatives

In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure–activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R² and R³ for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its : (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski ‘rule of five’, (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.     

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer’s Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Aβ1–40 peptide of several of these compounds were in the low-nanomolar range . The lowest K_i of 9.3 nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its ¹²³I-radiolabeled form ([¹²³I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood–brain barrier (BBB) to any significant extent.     

Brevistylumsides A and B,diterpene glycosides from Illicium brevistylum

A phytochemical investigation of 80% ethanol extract of Illicium brevistylum (Illiciaceae) resulted in the isolation of two new diterpene glycosides (1 and 2), together with three known diterpenes (3–5). The structures of the new compounds were deduced on the basis of comprehensive spectroscopic analysis including IR, HR-ESI–MS, ¹H NMR, ¹³C NMR, DEPT, COSY, HMBC and HSQC. The structures of known compounds 3–5 were identified by comparison of their spectral data with those reported in the literature.     

Characteristic lindenane sesquiterpenoid dimers and labdane diterpenoids from Chloranthus serratus

Chemical investigation on the roots of Chloranthus serratus (Chloranthaceae) afforded 11 terpenoids, including four lindenane-type sesquiterpenoid dimers (1–4), and seven labdane diterpenoids (5–11). The structures of these terpenoids were established by spectroscopic analysis (MS, ¹H, and ¹³C NMR). Compounds 4–11 were isolated from C. serratus for the first time. The chemotaxonomic significance of the isolated compounds was summarized herein.     

Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: Synthesis,pharmacological and simulation studies

Pyrazolealdehydes (4a–d), Knoevenagel’s condensates (5a–d) and Schiff’s bases (6a–d) of curcumin-I were synthesized, purified and characterized. Hemolysis assays, cell line activities, DNA bindings and docking studies were carried out. These compounds were lesser hemolytic than standard drug doxorubicin. Minimum cell viability (MCF-7; wild) observed was 59% (1.0 μg/mL) whereas the DNA binding constants ranged from 1.4 × 10³ to 8.1 × 10⁵ M^?1. The docking energies varied from ?7.30 to ?13.4 kcal/mol. It has been observed that DNA-compound adducts were stabilized by three governing forces (Van der Wall’s, H-bonding and electrostatic attractions). It has also been observed that compounds 4a–d preferred to enter minor groove while 5a–d and 6a–d interacted with major grooves of DNA. The anticancer activities of the reported compounds might be due to their interactions with DNA. These results indicated the bright future of the reported compounds as anticancer agents.     

Chemical constituents from Cymbaria dahurica L. (Scrophulariaceae)

Phytochemical study of Cymbaria dahurica L. afforded 16 compounds, including 12 flavonoids (1–12) and 4 iridoids (13–16). Structure elucidation of these compounds was generated by a combination of spectroscopic means (ESI-MS, ¹H and ¹³C NMR) and comparisons with the published data. This is the first report of isolation of compounds (1–6, 10–16) from C. dahurica and compounds (5, 10, 12) from the family Scrophulariaceae, respectively. The chemotaxonomic data can support the genus Cymbaria being accepted as a member of transitional taxa between the family Scrophulariaceae and Orobanchaceae.     

Chemical constituents from the rhizome of Menispermum dauricum DC. and their chemotaxonomic significance

The phytochemical investigations on the rhizome of Menispermum dauricum DC. led to the isolation of 18 compounds, including eleven alkaloids (1–11), four amides (12–15) and three fatty acids (16–18). All chemical structures were established on the basis of NMR (¹H NMR and ¹³C NMR) spectroscopic data. Meanwhile, compounds 5–6, 9–10 and 13–18 are reported for the first time from Menispermum genus, as well as the rhizome of Menispermum dauricum DC. Notably, this is the first study to report compounds 10, 15–18 from the family Menispermaceae. These compounds laid the foundation for the chemical classification of this species.     

New bis-thioglycosyl-1,1′-disulfides from Nasturtium officinale R. Br. and their anti-neuroinflammatory effect

As a part of our continuing search for bioactive constituents from Brassicaceae family, three new bis-thioglycosides (1–3) were isolated from the 80% MeOH extract of Nasturtium officinale, together with 13 known compounds (4–16). The chemical structures of three new bis-thioglycosides (1–3) were elucidated using NMR techniques (¹H and ¹³C NMR, ¹H–¹H COSY, HSQC, and HMBC), HRESIMS, and a chemical method. All the compounds were evaluated for their inhibitory effects on nitric oxide (NO) levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Among the isolates, compound 5 exhibited a strong inhibitory effect on NO production, and compounds 4 and 15 showed moderate inhibitory activities, suggesting the neuroprotective and anti-neuroinflammatory effects of bis-thioglycosides from N. officinale.     

Synthesis and characterization of new thiosemicarbazones,as potent urease inhibitors: In vitro and in silico studies

A new series of N-substituted thiosemicarbazones (3a-u) bearing 2-naphthyl and dihydrobenzofuranyl scaffolds were synthesized in good to excellent yields (78–95%). The synthesized compounds were characterized by advanced spectroscopic techniques, such as FTIR, ¹HNMR, ¹³CNMR and ESI-MS and evaluated as urease inhibitors. The structure of compound 3m was unambiguously confirmed by single crystal X-ray analysis. All compounds showed remarkable activities against urease enzyme with IC₅₀ values in range of 1.4–36.1 µM. The majority of the synthesized compounds showed higher activity than the standard compound thiourea. Molecular docking was performed to study the mode of interaction of these compounds and their structure-activity relationship. These studies revealed that the compounds bind at the active site and interacts with the nickel atom present in the binding site. The molecular docking demonstrated excellent co-relations with the experimental findings.     

Synthesis,in vitro urease inhibitory activity,and molecular docking studies of thiourea and urea derivatives

The current study deals with the synthesis of urea and thiourea derivatives 1–37 which were characterized by various spectroscopic techniques including FAB-MS, ¹H-, and ¹³C NMR. The synthetic compounds were subjected to urease inhibitory activity and compounds exhibited good to moderate urease inhibitory activity having IC₅₀ values in range of 10.11–69.80 µM. Compound 1 (IC₅₀ = 10.11 ± 0.11 µM) was found to be most active and even better as compared to the standard acetohydroxamic acid (IC₅₀ = 27.0 ± 0.5 µM). A limited structure–activity relationship (SAR) was established and the compounds were also subjected to docking studies to confirm the binding interactions of ligands (compounds) with the active site of enzyme.     

Synthesis,anticonvulsant and antimicrobial activities of some new 2-acetylnaphthalene derivatives

In this study, as a continuation of our research for new (arylalkyl)imidazole anticonvulsant compounds, the design, synthesis and anticonvulsant/antimicrobial activity evaluation of a series of 2-acetylnaphthalene derivatives have been described. Molecular design of the compounds has been based on the modification of nafimidone [1-(2-naphthyl)-2-(imidazol-1-yl)ethanone], which is a representative of the (arylalkyl)imidazole anticonvulsant compounds as well as its active metabolite, nafimidone alcohol (3, 4). In general, these compounds were variously substituted at the alkyl chain between naphthalene and imidazole rings and subjected to some other modifications to evaluate additional structure–activity relationships. The anticonvulsant activity profile of those compounds was determined by maximal electroshock seizure (MES) and subcutaneous metrazol (scM) seizure tests, whereas their neurotoxicity was examined using rotarod test. All the ester derivatives of nafimidone alcohol (5a–h), which were designed as prodrugs, showed anticonvulsant activity against MES-induced seizure model. Four of the most active compounds were chosen for further anticonvulsant evaluations. Quantification of anticonvulsant protection was calculated via the ip route (ED₅₀ and TD₅₀) for the most active candidate (5d). Observed protection in the MES model was 38.46 mg kg^?1 and 123.83 mg kg^?1 in mice and 20.44 mg kg^?1, 56.36 mg kg^?1 in rats, respectively. Most of the compounds with imidazole ring also showed antibacterial and/or antifungal activities to a certain extent in addition to their anticonvulsant activity.     

Bioactive triterpenoids from twigs of Betula schmidtii

Investigation of the MeOH extract of Betula schmidtii twigs resulted in the isolation and identification of three new triterpenoids (1–3), along with ten known ones (4–13). The structures of new compounds (1–3) were elucidated by spectroscopic methods, including 1D, 2D NMR (¹H and ¹³C NMR, COSY, HSQC, HMBC, and NOESY), HR-MS, and chemical methods. All the isolated compounds were evaluated for their cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines. Compound 11 exhibited potent cytotoxic activities against four cell lines, and compounds 5 and 13 significantly induced nerve growth factor secretion in a C6 rat glioma cell line. Their anti-inflammatory effects were also assessed by measuring nitric oxide production in lipopolysaccharide–activated BV-2 cells. Compounds 7 and 12 displayed potent inhibition of nitric oxide production, without significant cell toxicity.     

Synthesis, in vitro and in silico studies of novel potent urease inhibitors: N-[4-({5-[(3-Un/substituted-anilino-3-oxopropyl)sulfanyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-thiazol-2-yl]benzamides

The present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (2) in weak basic aqueous medium followed by hydrazide formation, 4, and cyclization with CS₂ to reach the parent bi-heterocyclic nucleophile, N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (5). Various electrophiles, 8a–l, were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a–l. The structures of the newly synthesized products were corroborated by IR, ¹H NMR, ¹³C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j, with IC₅₀ value of 2.58?±?0.02?µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC₅₀ value of 21.11?±?0.12?µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (9a–l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (?7.10?kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors.     

Parallel synthesis of potent dopaminergic N-phenyltriazole carboxamides applying a novel click chemistry based phenol linker

Taking advantage of our click chemistry based methodology to construct novel SPOS (solid phase organic synthesis) resins, the triazolylmethyl linked catechol 6a was discovered, which is readily available via copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of azidomethyl substituted polystyrene with O-propargylcatechol and can be applied for the parallel synthesis of N-phenyltriazole carboxamides. As a proof-of-concept, a ‘catch-and-release’ strategy could be successfully applied for a parallel synthesis of dopaminergic phenyltriazoles of type 2. A focused model library of 20 test compounds revealing three points of diversity was generated by a three-step SPOS approach. Product purification was performed employing a solid-supported carboxylic acid anhydride as a scavenger. GPCR-ligand binding screening revealed dopamine D3 receptor ligands with K_i values in the single digit nanomolar range.