Synthesis,in-vivo anti-diabetic & anticancer activities and molecular modelling studies of tetrahydrobenzo[d]thiazole tethered nicotinohydrazide derivatives

A series of thirty new thiazole-pyridine derivatives were synthesized by reaction of 4,4,7,7-tetra-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine with 6-chloronicotinate followed by condensing with benzaldehydes and screened for their anti-diabetic activity by in vivo housing Swiss albino mice. All synthesized compounds resulted in reducing the glucose level when compared with reference standard drug glibenclamide. In specific, compound 7 exhibited significant activity in terms of fasting blood glucose level reduction. In addition, the in-silico binding studies of the potential compounds 11f and 11g with human PPAR-γ protein complexed with Retinoid X Receptor (RXR) alpha Nuclear Receptor showed good interactions when compared to the standard drug Rosiglitazone. The newly synthesized drugs may be potential anti-diabetic drugs with possible specific actions.     

Synthesis of 2,3,4-trideoxy-4-c-(phenylphosphinyl)-dl-glycero-pentofuranose and its 1,5-diacetate

Synthesis of 2,3,4-trideoxy-4-C-(phenylphosphinyl)-dl-glycero-pentofuranose (11) starting from 2-furanmethanol was successful. The reaction of methyl 2,3-dideoxy-(1S)-dl-pentopyranosid-4-ulose 4-(p-toluenesulfonylhydrazone) with methyl phenylphosphonite gave methyl (4RS)-2,3,4-trideoxy-4-C-[(methoxy)phenylphosphinyl]-4-C-(p-toluenesulfonylhydrazino)-(1S)-dl-pentopyranoside (7), which on treatment with sodium borohydride afforded methyl 2,3,4-trideoxy-4-C-[(methoxy)phenylphosphinyl]-(1S)-dl-glycero-pentopyranoside (9). Treatment of compound 9 with SDMA followed by hydrolysis and treatment with acetic anhydride-pyridine afforded 1,5-diacetate 12 of compound 11.     

First cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides

The halogenated 1H-1,2,4-triazole glycosides 6-10 were synthesized by BF₃-activated glycosylation of 3(5)-chloro-1,2,4-triazole (2), 3,5-dichloro-1,2,4-triazole (3), 3,5-dibromo-1,2,4-triazole (4), and 3(5)-bromo-5(3)-chloro-1,2,4-triazole (5) with 1,2,3,4-tetra-O-pivaloyl-β-d-xylopyranose (1). The β-anomeric major products 3-chloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (6β), 3,5-dichloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (7β), and 3,5-dibromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (8β) were used as starting materials for transition metal catalyzed C-C-coupling reactions. Arylations of the triazole ring of 7β, and 8β were successful in 5-position with phenylboronic acid, 4-vinylphenylboronic acid, and 4-methoxyphenylboronic acid, respectively, under Suzuki cross-coupling conditions (products 11-17). Moreover, a Cu-catalyzed perfluoroalkylation of 8β is reported with 1-iodo-perfluorohexane yielding 3-perfluorohexyl-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (18). Compound 18 was depivaloylated to the trihydroxy derivative 19. The copper-mediated reaction of 8β with Rupert's reagent gave the bis(3-bromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazol-5-yl) (20).     

Synthesis,characterization and reactivity of pentacarbonyl(η1-2,4-pentadienyl)manganese

Reaction of NaMn(CO)₅ with trans-1-bromopenta-2,4-diene in tetrahydrofuran at −78°C gives (η¹-2,4-pentadienyl)Mn(CO)₅ (1) in excellent yield. Compound 1 undergoes η¹ → syn-η³ → η⁵ transformation and, yields (syn-η³-2,4-pentadienyl)Mn)(CO)₄ (2) and (η⁵-pentadienyl)Mn(CO)₃ (3), respectively. The reactions of 1 with the electrophiles tetracyanoethylene (TCNE) and sulfur dioxide (SO₂) were investigated. Compound 1 undergoes a [4 + 2] cycloaddition with TCNE and an insertion reaction with SO₂. The product are characterized by elemental analysis and spectroscopic data.     

Conduramine F-1 epoxides: synthesis and their glycosidase inhibitory activities

Starting from (±)-7-oxanorbornenone ((±)-14), (±)-(1RS,2RS,3SR,6SR)-6-azidocyclohex-4-en-1,2,3-triol ((±)-24) and (±)-(1RS,2RS,3SR,6RS)-6-azidocyclohex-4-en-1,2,3-triol ((±)-26) were obtained. Epoxidation of the latter cyclohexene derivative gave two epoxides (±)-30 and (±)-31 that were converted into (±)-conduramine F-1 epoxides (±)-10 and (±)-11 and N-substituted derivatives (±)-12 and (±)-13. Compound (±)-(1RS,2SR,3RS,4SR,5RS,6SR)-5-({[4-(trifluoromethyl)phenyl]methyl}amino)-7-oxabicyclo[4.1.0]heptane-2,3,4-triol ((±)-12c) is a good, non-competitive inhibitor of β-xylosidase from Aspergillus niger (K_i=2.2 μM), and (±)-(1RS,2RS,3SR,4RS,5SR,6SR)-5-{[(biphenyl-4-yl)methyl]amino}-7-oxabicyclo[4.1.0]heptane-2,3,4-triol ((±)-13d) is a good inhibitor of α-glucosidase from brewer's yeast (K_i=2.8 μM, non-competitive).     

Stereoselective conjugate addition of TMSI-activated butylcopper to 1-(R)-endo-(1-naphthyl)bornyl crotonate

Conjugate addition of butylcopper/iodotrimethylsilane to naphthylbornyl crotonate (1) at −60°C gives 1-[1-(R)-endo-(1-naphthyl)]bornyl [(S)-3-methyl]-heptanoate (2) in 93% yield and 98% diastereomeric excess. The addition of TMSI-activated butylcopper is faster at −60°C than that of lithium dibutylcuprate (LiBu₂Cu).     

Synthesis,in-silico antiviral screening and in-vitro antibacterial screening of a novel chalcone derivatives

A new series of novel chalcones was synthesized and subjected to screening of theoretical molecular and biological properties. For evaluating the theoretical molecular properties of these molecules Molinspiration and Osiris software were used. It was concluded from data that the majority of molecules exhibited theoretical molecular and biological properties similar to that of standard drugs. Role of Hemagglutinin is vital during the attack of virus on cells so Hemagglutinin inhibitors may act as potent antiviral agents. Considering this fact in-silico studies were performed using the SwissDock screening engine on Hemagglutinin target PDB code 1HGH. Hemagglutinin inhibition potential in terms of binding affinity was expressed as ΔG values ranging from −8.71 kcal/mol to −7.39 kcal/mol. Compound IIIm showed maximum binding affinity with ΔG value −8.71 kcal/mol followed by compound IIIj ΔG value −8.31 kcal/mol. It's prudent from ΔG values that compounds may act as potent antiviral agents. Compounds were also screened for in-vitro antibacterial activity against five pathogenic strains. Most of the compounds exhibited low to moderate activity against strains under study. Compound IIIn demonstrated good activity against four pathogenic strains with highest zone of inhibition of 16 mm against K. pneumoniae and S. typhi.     

Synthesis of (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone and (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone as colchicine mimetics

Colchicine mimetic (±)-4S,5R-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene (1) was epoxidized to afford a mixture of epoxides. The epoxides were separately converted in two steps, with high stereoselectivity, to two regioisomeric α-methoxyketones. One regioisomer, (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone (17), proved to be about 12-fold more potent than synthetic precursor 1 against HCT-116 tumor cells while the other regioisomer, (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone (16), and the synthetic intermediates tested showed no improvement in potency.     

Synthesis and anticancer study of 9-aminoacridine derivatives

Acridine and its derivatives, well known as DNA intercalates lead to cell cycle arrest and apoptosis. 9-Aminoacridine derivatives were synthesized, characterized and evaluated against lung cancer (A-549) cell line and cervical cancer (HeLa) cell line by MTT assay. Compound 9 exhibited potent anticancer activity with CTC₅₀ (13.75 & 18.75 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. In vitro short term cytotoxicity evaluation of compound 9 was carried out by Dalton’s Lymphoma Ascites (DLA) with percentage growth inhibition CTC₅₀ (337.5 μg/ml). Compound 7 also exhibited good anticancer activity with CTC₅₀ (31.25 & 36.25 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. Further in vivo study of newly synthesized 9-aminoacridine derivative can give a ray of light in the field of anticancer drugs.     

Hyperterpenoids A and B: Two pairs of unprecedented 6/6/4/6/6 polycyclic cyclobutane meroterpenoids with potent neuroprotective and anti-inflammatory activities from Hypericum beanii

Hyperterpenoid A (1) and B (2), two pairs of enantiomers, with an unprecedented 6/6/4/6/6 polycyclic skeleton, along with one known compoud hypermonone A (3) were isolated from Hypericum beanii. The racemate (±)-1 and (±)-2 were successfully separated into the two optically pure enantiomers (ee ≥ 99%) using a preparative HPLC system. Their absolute configurations were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction method. The related plausible biogenetic pathways were presented. Compound 1-3 showed significant neuroprotective activity and potential anti-inflammatory activity. The result that (+)-2 and (-)-2 presented different anti-inflammatory properties, may lead us to new discovery of structure activity relationship between racemates, enantiomers, and diastereomers, as well as further research regarding the binding of drugs to target proteins.     

Crystallographic Studies of Cesium Tetrafluorobromates(III)

This article describes CsBr₂F₇ (1) which has been obtained in the form of colorless single crystals. Shown by the X-ray diffraction on single crystals its Br₂F₇⁻ anion is neither planar nor is its Br−μ-F−Br unit linear, as previously deduced from Raman spectra. Also a regular tetrafluorobromate CsBrF₄ (2) has been obtained in the form of a colorless powder. Compound 2 can also be obtained from compound 1 by evacuation. The crystal structure of CsBrF₄ (2) has been elucidated by the Rietveld refinement on its X-ray powder pattern.     

Four new constituents from Taraxacum mongolicum

Two new flavone glycosides,isoetin-7-O-β-D-glucopyranosyl-2′-O-α-L-arabinopyranoside (1) and isoetin-7-O-β-D-glucopyr- anosyl-2′-O-α-D-glucopyranoside (2),a new lignan,mongolicumin A (3),and a new guaianolide,mongolicumin B (4) were isolated from the aerial part of Taraxacum mongolicum.Their structures were elucidated mainly by spectral analyses.     

Meloslines A and B,two novel indole alkaloids from Alstonia scholaris

An unprecedented indole alkaloid melosline A (1), with 6/5/6/6 tetracyclic ring skeleton, together with a new alkaloid melosline B (2) and one known compound (3) were isolated from the leaves and twigs of Alstonia scholaris. The new structures were elucidated by comprehensive spectroscopic analysis. The absolute configuration of compound 1 was confirmed by comparison of experimental data with calculated electronic circular dichroism (ECD). Compound 1 exhibited moderate cytotoxicity against MCF-7 cancer cell lines.     

New biologically active linear triterpenes from the bark of three new-caledonian Cupaniopsis species

In the course of automated screening for small-molecule agonists to peroxisome proliferator-activated receptor-γ (PPAR-γ), 10 new linear triterpenes 1-10 have been isolated from the bark of three neocaledonian Cupaniopsis species, SAPINDACEAE. The structures were elucidated by extensive mono- and bi-dimensional spectroscopy and mass spectrometry.     

Synthesis of glutamic acid and glutamine peptides possessing a trifluoromethyl ketone group as SARS-CoV 3CL protease inhibitors

Trifluoromethyl-β-amino alcohol 11 [(4S)-tert-butyl 4-amino-6,6,6-trifluoro-5-hydroxyhexanoate] was synthesized in five steps starting from Cbz-l-Glu-OH 5 where the key step involved the introduction of the trifluoromethyl (CF₃) group to oxazolidinone 7, resulting in the formation of silyl ether 8 [(4S,5S)-benzyl 4-(2-(tert-butoxycarbonyl)ethyl)-5-(trifluoromethyl)-5-(trimethylsilyloxy)oxazolidine-3-carboxylate]. Compound 11 was then converted into four tri- and tetra-glutamic acid and glutamine peptides (1-4) possessing a CF₃-ketone group that exhibited inhibitory activity against severe acute respiratory syndrome coronavirus protease (SARS-CoV 3CL^pro).     

Synthesis and goat pulmonary vasodilatory activity of some novel 1,3,4-oxadiazoles

A novel series of[(1Z)-1-(2,2-disubstituted-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl) ethylidene] (PSMB1–PSMB15) were synthesized as title compounds. The synthesis route included the cyclization of carbonyl hydrazone in the presence of excess of acetic anhydride and subsequent condensation with various aromatic amines. All the title compounds were characterized by IR, ¹H NMR, MS and elemental analysis. They were screened for their goat pulmonary vein relaxant activity. Compound PSMB9 was found the most active derivative exhibiting 83.33% relaxation. Isosorbide dinitrate was used as the standard drug for goat pulmonary vein relaxant activity.     

Synthesis of the two enantiomers of the sex pheromone of Diabrotica Undecimpunct at a Howardi and of chiral precursors of other pheromones starting from enantiomerically pure methyl hydrogen (R)-3-methylglutarate

Readily available methyl hydrogen (R)-3-methylglutarate(2) is a useful chiral building block for the synthesis of several biologically active compounds. Enantiomerically pure (R)-2 has been employed to synthesize stereospecifically each of the two enantiomers, 1a and 1b, of 10-methyl-2-tridecanone, the sex pheromone of the southern corn rootworm, Diabrotica undecimpunctata howardi Barber. Compound (R)-2 has been also used to prepare 99% optically pure (R)-3-methyl-1-pentanol (6) and enantiomerically pure (R)-5-methyl-i-tricosyne (7). These compounds are useful building blocks suitable for the further elaboration to other chiral insect pheromones.     

Triarylamine-combined nitronyl nitroxide and its hole-transporting property

N,N-Bis(4-methoxyphenyl)-4-(1-oxyl-3-oxide-4,4,5,5-tetramethylimidazolin-2-yl)phenylamine (1) was synthesized as a durable nitronyl nitroxide radical combined with a triarylamine moiety. Cyclic voltammetry and UV–Vis absorption spectra during the electrochemical oxidation of 1 revealed that the first redox was derived from the triarylamine moiety. The ionization potential of 1 was measured by photoelectron spectroscopy to be −5.4 eV, which was appropriate as a hole-transporting material. A single-layer hole-only device was fabricated with the radical molecule 1 dispersed in polycarbonate (ITO/1:polycarbonate/Al): The radical-layer exhibited a maximum current density of 0.2 mA/cm², which was applicable for organic electronic devices.     

Efficient and versatile synthesis of (2S,3R)-sphingosine and its 2-azido-3-O-benzylsphingosine analogue

The title compounds (1, 2) were synthesized from (2R,3S)-2-O-benzyl-3,4-O-(3′-pentylidene)-2,3,4-trihydroxybutanal (5). Installation of the E-double bond and aliphatic chain into the sphingosine base was effected by a sequence of Horner-Wadsworth-Emmons olefination of 5, conversion to allylic acetate 8, and copper-mediated Grignard coupling. The method is versatile, allowing a broad variety of aliphatic chains to be introduced in the organocuprate coupling step.     

Incorporation of 5-substituted uracil derivatives into nucleic acids—III : Synthesis of 5-substituted uracils derived from 5-acetyluracil

5-Acetyluracil (1) has been converted into 5-(bromoacetyl)-uracil (2) by an established procedure. Reduction of 2 with sodium borohydride gave 5-(2-hydroxyethyl)uracil (4) in low yield. Treatment of 5-vinyluracil (7), obtained from 1 by published methods, with 1 molecular proportion of bromine followed by heating to 100°, gave E-5-(2-bromovinyl)uracil (8). Reaction of 8 with potassium t-butoxide gave 5(7)H-furanol[2,3,d]pyrimidin-6-one (10) and upon reduction with sodium in liquid ammonia, 8 gave 5-ethyluracil (11). Compound 2 showed low antibacterial activity against Staphylocuccus aureus, Streptococcus faecalis and Escherichia coli in nutrient broth and in a medium containing only inorganic salts, glucose and thymine, appreciable activity (～ 6 μg/ml) against E. coli. Compound 2 was not incorporated into the DNA of E. coli.