Osteogenic constituents from Pterospermum acerifolium Willd. flowers

Phytochemical investigation of ethanol extracts of the Pterospermumacerifolium flowers led to the isolation and identification of two new flavones, 4′-(2-methoxy-4-(1,2,3-trihydroxypropyl) phenoxy luteolin (1) and 5,7,3′-trihydroxy-6-O-β-d-glucopyranosyl flavone (2), and one new lactone, 3,5-dihydroxyfuran-2(5H)-one (3) along with 14 known compounds (4-17). The structure of compounds 1-17 was established based on MS, 1D and 2D NMR, spectroscopic analysis. Eight of these compounds (1-6, 8 and 9) were assessed for osteogenic activity by using primary cultures of rat osteoblast. The compounds 1, 3 and 4 significantly stimulated osteoblast differentiation and mineralization as evident from a marked increase in expression of alkaline phosphatase and alizarin red-S staining of osteoblasts.     

Osteogenic activity of diphenyl ether-type cyclic diarylheptanoids derived from Acer nikoense

Osteogenic activity of six diarylheptanoids, acerogenin A (1), (R)-acerogenin B (2), aceroside I (3), aceroside B₁ (4), aceroside III (5) and (−)-centrolobol (6) and two phenolic compounds; (+)-rhododendrol (7) and (+)-cathechin (8), isolated from the stem bark of Acer nikoense (Nikko maple) was evaluated using alkaline phosphatase (ALP) activity as a marker for early osteoblast differentiation. We found that the diphenyl ether-type cyclic diarylheptanoids 1-5 promoted ALP activity in mouse preosteoblastic MC3T3-E1 cells without affecting cell proliferation, but linear-type diarylheptanoid 6 and phenolic compounds 7 and 8 did not. Diphenyl ether-type cyclic diarylheptanoids 1-4 also increased protein production of osteocalcin, a late stage maker for osteoblast differentiation, and induced osteoblastic mineralization. Structure-activity relationships of these compounds demonstrated that the stimulative efficacy of aglycones was higher than that of its glycosides. Taken together, diphenyl ether-type cyclic diarylheptanoids promote early- and late-stage osteoblastogenesis, which may open the possibility for the development of novel osteogenic agents.     

Substituted imidazole derivatives as novel cardiovascular agents

A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c, 3b, 3c, 3f, 4a, 4b and 4c) have shown good hypotensive and bradycardiac responses. Compounds 3b, 3c, 3f and 4c have shown better activity than reference drug clonidine. All the compounds have shown ALD50 >1000 mg/kg with maximum in 2e and 4c (>1200 mg/kg).     

Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor

Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC₅₀ values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.     

Dopamine release and molecular modeling study of some coumarin derivatives

4-aryl-2-amino-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitrile (1), 4-aryl-2-oxo-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitriles (2a-2c), 3-(6-aryl-1,2,5,6- tetrahydro-2-thioxopyrimidin-4-yl)-4-hydroxy-2H-chromen-2-one (3a, 3b) and pyrazol-3-yl-4-hydroxycoumarin derivatives (4a-4c, 5, 6a, 6b, 7a, 7b, and 8a-8c) were prepared in order to measure their % change dopamine release in comparison to amphetamine as reference, using PC-12 cells in different concentrations. In addition, the molecular modeling study of the compounds into 3BHH receptor was also demonstrated. The calculated inhibition constant (k_i) implemented in the AutoDock program revealed identical correlation with the experimental results to that obtained binding free energy (ΔG_b) as both parameters revealed reasonable correlation coefficients (R²) being 0.51 involving 10 compounds; (1, 2b, 2c, 3a, 3b, 4a, 4b, 6a, and 8c).     

Thermal solvent-free synthesis of novel pyrazolyl chalcones and pyrazolines as potential antimicrobial agents

A novel approach was adopted for the synthesis of series of new pyrazolyl chalcones (3a-c) by the reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) with different 5-acetylbarbituric acid derivatives (2a-c) under thermal solvent-free condition. The chalcones were then converted to the corresponding pyrazolines (4a-c) under the same condition in excellent yields. All the synthesized compounds were characterized using elemental analysis and spectral data (IR, ¹H NMR, and mass spectrometry). The synthesized compounds were tested for their antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds (3a-4c) showed good antibacterial and antifungal activities, respectively. Among the screened compounds, 3b showed more potent inhibitory activity (MIC = 12.5 μg/ml) nearly to that of standard antibiotics ciprofloxacin, griseofulvin and fluconazole.     

Synthesis, characterization of [{(N-methyl-N-benzyl)amino}methyl]ferrocenes and their cyclopalladated complexes: Crystal structure of σ-Pd[(η-C5H5)Fe(η-C5H3CH2N(CH3)CH2C6H4NO2-4)]Cl(PPh3)

Condensation of aminomethylferrocene (1) and substituted benzaldehydes resulted in aldimines 2a-c which followed by reduction with sodium borohydride to give 3a-c. N-methylation of 3a-c with HCHO/NaCNBH₃/HOAc led to 4a-c. Treatment of 4a-c with sodium palladium tetrachloride in the presence of sodium acetate afforded cleanly cyclopalladated 5a-c in which configurations consisted of the R_NR_C, S_NS_C. The preferable activation of C_Ferrocenyl-H bond over C_Phenyl-H bond was also observed. All compounds 2-5 were characterized by elemental analysis, IR and ¹H NMR. In addition, the molecular structure of 5c was confirmed by single crystal X-ray diffraction. The possible mechanism for the formation of 5 was also discussed.     

Synthesis, characterization of strontium-bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate

The strontium salts Sr(cholate)₂, (Compound 1), Sr(dehydrocholate)₂, (Compound 2) and Sr₃(3-dehydrocholanoyliden-l-tartrate)₂, (Compound 3) have been prepared and characterized. The potential anti-osteoporotic activity of these compounds was tested on human primary osteoblasts (hOBs) and human primary osteoclasts (hOCs) in comparison with the bioactivity of strontium ranelate, previously registered as drug in the treatment of post-menopausal osteoporosis. Our results led to the hypothesis that the tested compounds, particularly Compound 2, may have requirements for modulating skeletal tissue regeneration or at least down regulating the loss of bone mass. In fact, all tested compounds have been shown to induce maturation in human primary osteoblasts (hOBs) and apoptosis of human primary osteoclasts (hOCs) at the same time.     

Regioselective facile one-pot Friedländer synthesis of sugar-based heterocyclic biomolecules

Regioselective facile one-pot synthesis of 16 different sugar-based quinoline, naphthyridine, and xanthone derivatives is reported. The compounds are characterized by NMR spectroscopy and elemental analysis. The β-Anomeric form of the sugar moiety was identified from ¹H NMR studies. Antimicrobial studies of these sugar-heterocyclic derivatives, 3a, 3b, 3f, 5c, 7a, 7b, and 7c show excellent activity against different microbes.     

Exploring new near-infrared fluorescent disulfide-based cyclic RGD peptide analogs for potential integrin-targeted optical imaging

We synthesized disulfide-based cyclic RGD pentapeptides bearing a near-infrared fluorescent dye (cypate), represented by cypate-c(CRGDC) (1) for integrin-targeted optical imaging. These compounds were compared with the traditional lactam-based cyclic RGD counterpart, cypate-c(RGDfK) (2). Molecular modeling suggests that the binding affinity of 2 to integrin α_vβ₃ is an order of magnitude higher than that of 1. This was confirmed experimentally, which further showed that substitution of Gly with Pro, Val and Tyr in 1 remarkably hampered the α_vβ₃ binding. Interestingly, cell microscopy with A549 cells showed that 1 exhibited higher cellular staining than 2. These results indicate that factors other than receptor binding affinity to α_vβ₃ dimeric proteins mediate cellular uptake. Consequently, 1 and its analogs may serve as valuable molecular probes for investigating the selectivity and specificity of integrin targeting by optical imaging.     

Probing the active site of rat porphobilinogen synthase using newly developed inhibitors

The structurally related tetrapyrrolic pigments are a group of natural products that participate in many of the fundamental biosynthetic and catabolic processes of living organisms. Porphobilinogen synthase catalyzes a rate-limiting step for the biosyntheses of tetrapyrrolic natural products. In the present study, a variety of new substrate analogs and reaction intermediate analogs were synthesized, which were used as probes for studying the active site of rat porphobilinogen synthase. The compounds 1, 3, 6, 9, 14, 16, and 28 were found to be competitive inhibitors of rat porphobilinogen synthase with inhibition constants ranging from 0.96 to 73.04 mM. Compounds 7, 10, 12, 13, 15, 17, 18, and 26 were found to be irreversible enzyme inhibitors. For irreversible inhibitors, loose-binding inhibitors were found to give stronger inactivation. The amino group and carboxyl group of the analogs were found to be important for their binding to the enzyme. This study increased our understanding of the active site of porphobilinogen synthase.     

Unsymmetric diruthenium complexes

The new diruthenium complexes trans-[(NH₃)₅Ru(L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₅ (L-L are the bridging ligands pyrazine, 2a; 4,4′dipyridyl, 2b; and trans-1,2-bis(4-pyridyl)-ethylene, 2c; bpy-Me is N-methyl-pyridyl-pyridinium) are generated from the new complexes (L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₃ (1a-c) and [(NH₃)₅Ru(H₂O)](PF₆)₂. Cyclic voltammetry on the new compounds in acetonitrile electrolyte reveals two quasi-reversible oxidation steps corresponding to the two Ru^II/III couples in 2b and 2c and a single oxidations for 1a-c. In addition, two reduction waves are observed for the bpy-Me ligands of 1a-c and 2a-c. All of the new compounds exhibit multiple metal-to-ligand charge transfer (MLCT) bands in the visible region of the spectrum. For compounds 1a-c the most intense absorption in the visible region decreases in energy as the length of the aromatic bridging ligands increases. By contrast the strongest absorption band of 2a is lower in energy than the most intense bands of both 2b and 2c. Single crystal X-ray analysis of 2a reveals that the bridging pyridine is coplanar with the pyridyl ring of the bpy-Me ligand that is attached to the Ru center. DFT calculations on 2a indicate that the HOMO is localized predominately on the {(NH₃)₅Ru-pyz-Ru(NH₃)₄} portion of the complex and the LUMO has slightly more contribution from the bpy-Me ligand.     

Biological evaluation of 3'-O-alkylated analogs of salacinol, the role of hydrophobic alkyl group at 3' position in the side chain on the α-glucosidase inhibitory activity

Four analogs with 3′-O-alkyl groups (9a: CH₃, 9b: C₂H₅, 9c: C₁₃H₂₇ or 9d: CH₂Ph) instead of the 3′-O-sulfate anion in salacinol (1), a naturally occurring potent α-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-d-arabinitols (18a and 18b) with appropriate epoxides (10a-10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal α-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used α-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3′ position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes.     

Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl analogues of 5-fluorouracil, N-benzoyl adenine, uracil, thymine, N-benzoyl cytosine and evaluation of their antitumor activities

The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N⁶-benzoyl adenine (6b), uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N⁶-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a,b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.     

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles

Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 μg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100 μg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, ¹H NMR, and ¹³C NMR data.     

Selective leishmanicidal effect of 1,3,4-thiadiazole derivatives and possible mechanism of action against Leishmania species

With the aim of determining selectivity and the possible target(s) of nitroheteroaryl-1,3,4-thiadiazoles considered as possible leads for the development of anti-leishmanial agents, we studied 5-nitroimidazole, 5-nitrofuran and 5-nitrothiophene analogs of N-substituted-piperazinyl-1,3,4-thiadiazoles. We investigated 21 representative compounds 1-3(a-g) for the following properties: selectivity and efficiency against different Leishmania wild type species and intracellular parasite, toxicity against host cells and inhibition of topoisomerases I and II. Our results indicate that the nitroimidazole analogs 1a and 1f, and nitrofuran derivatives 2a, 2b, 2c, 2f, and 2g exhibited low toxicity against the host cells (IC₅₀ ? 80 μM), but high selectivity against intracellular amastigotes (selectivity index > 12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC₅₀ doses of compounds against Leishmania). Our findings showed that at least part of leishmaniacidal effect of the compounds could be attributed to disruption DNA-relaxed activities of topoisomerases I and II, and cleavable-complex formation.     

Synthesis and evaluation of the platelet antiaggregant properties of phenolic antioxidants structurally related to rosmarinic acid

Polyphenols, such as rosmarinic acid, are widely distributed natural products with relevant antioxidant activity. Oxidative stress plays an important role in the pathogenesis of a number of disorders. Here, we report on the synthesis and biological effects of the polyphenolic esters hydroxytyrosyl gallate (1), hydroxytyrosyl protocatechuate (2) and hydroxytyrosyl caffeate (3), structurally related to rosmarinic acid. The three compounds showed a greater free radical scavenging activity than their precursors and also than rosmarinic acid. Esters 1 and 3 significantly reduced thrombin-evoked platelet aggregation, which is likely mediated to the attenuation of thrombin-stimulated Ca²⁺ release and entry. The three compounds reduced the ability of platelets to accumulate Ca²⁺ in the intracellular stores, probably by enhancing the Ca²⁺ leakage rate and reduced store-operated Ca²⁺ entry in these cells. These observations suggest that the structurally-simplified analogs to rosmarinic acid, compounds 1 and 3, might be the base of therapeutic strategies to prevent thrombotic complications associated to platelet hyperaggregability due to oxidative stress.     

β-Diketiminato 3d-metal compounds: Synthesis, characterization and catalytic behavior towards ethylene

The lithium β-diketiminate (1c, [Li{N(2,6-ⁱPr₂C₆H₃)C(Ph)CHC(^tBu)NH}]₂ represented as (LiL)₂) reacted with 3d-metal (II) chlorides to afford the corresponding compounds (2-7). All metal compounds were fully characterized by elemental, spectroscopic analyses and the single-crystal X-ray diffraction. The coordination geometries around the metals are shown to be tetrahedral within the trinuclear Co₂Li compound (2), planar in ML₂ (M = Co, 3), pseudo-tetrahedral conformation in the ML₂ with M as Mn (4), Fe (5) or Zn (6), and square planar in the dinickel compound (7). Indicated by the trimetallic Co₂Li compound 2, a six-membered ring is constructed of three metal atoms and three bridged chlorides as a twisted conformation. An inversion center is present in the centroid of the Ni₂Cl₂ four-membered ring within compound 7. The plausible mechanism of forming ML₂ was proposed through the chloro-bridged multinuclear compounds on the basis of isolated intermediates of trinuclear (2) and dinuclearic (7) compounds. Upon treatment with methylaluminoxane (MAO), the nickel compound 7 possessed good activity towards ethylene oligomerization, whereas the other metal compounds showed moderate activities towards ethylene polymerization.