Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir

We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO₂R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)₂ group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC₅₀ value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 μM in KB or HFF cells.     

Perfluoroalkylated derivatives of 6-deoxy-6-ethylamino-d-galactose, 1-deoxy-1-methylamino-d-glucitol, and 1-amino-1-deoxy-d-glucitol: syntheses, hemocompatibility, and effect on perfluorocarbon emulsion

N-Polyfluoroalkyl derivatives of 6-deoxy-6-ethylamino-1,2;3,4-di-O-isopropylidene-α-d-galactopyranose (8-10), 1-deoxy-1-methylamino-d-glucitol (13-15), and 1-amino-1-deoxy-d-glucitol (16-18), all possessing perfluoroalkyl segment, were prepared using nucleophilic epoxide ring opening of 2-[(perfluoroalkyl)methyl]oxiranes 1-3. Co-emulsifying properties and hemolytic activity of the new perfluoroalkylated amphiphiles were tested. Both types of the polyol derivatives 8-10 and 13-18 generally displayed good to excellent co-emulsifying properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. Mono-perfluoroalkylated compounds 8-10 and 13-15 displayed high hemolysis, whereas acyclic bis-perfluoroalkylated compounds 16-18 were non-hemolytic even for short perfluorobutyl segment (16). The properties were generally improving with increasing perfluoroalkyl chain length.     

Nonenzymic,biogenetic-like cyclization of a trienic acetal

The stereoselective synthesis of the trans,trans trienic acetal 9 is described. Alkylation of the lithio derivative of 2-methyl-1-hexene-5-yne (10) with ethylene oxide gave the acetylenic alcohol 11, which on reduction with sodium in liquid ammonia afforded the trans diene 12. Alkylation of the sodium enolate of acetylacetone with 13, the mesylate derived from 12, gave the dione 14; chlorination of 14 and deacylation of the resulting chloro dione 15 provided the α-chloro ketone 16. Conversion of 16 to the trans,trans acetal 9 was accomplished by means of a Cornforth olefin synthesis. Thus, stereoselective attack by the Grignard reagent derived from 1-ethylenedioxy-4-chlorobutane afforded from 16 the chlorohydrin 17, which on treatment with methanolic base was converted to the trans epoxide 18. Deoxygenation of 18 to give the trans,trans acetal 9 was accomplished via the intermediacy of the iodohydrin 19.     

Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes

The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.     

Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates: Potent, non-cytotoxic, antiapoptotic agents

Compounds containing a quinone moiety represent an important class of biologically active molecules that are widespread in nature, displaying anticancer, antibacterial, antimalarial, and fungicidal activities. In the course of designing 2,3-disubstituted-1,4-naphthoquinones derivatives as potential cysteine protease inhibitors, two naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates, 1a and 1b, were obtained. The antiapoptotic potential of 1a and 1b was then evaluated and compared to that of naphthoquinone 4. Primary rat hepatocytes were incubated with synthesized naphthoquinone derivatives and then exposed to the apoptotic stimulus camptothecin. Our results indicate that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b exerted a potent protective role in camptothecin-induced apoptosis in primary rat hepatocytes. Both 1a and 1b significantly increased cell viability, while reducing nuclear fragmentation, caspase-3, -8 and -9 activation, and cytochrome c release induced by camptothecin. In addition, 1a and 1b were shown to up-regulate Bcl-X_L, a pro-survival member of the Bcl-2 family of proteins, which modulates the mitochondrial pathway of apoptosis. Similar protective effects of quinone derivatives were seen in HuH-7 and PC12 cells incubated with distinct apoptotic stimuli, such as camptothecin, TGF-β1, or rotenone. Our results suggest that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b may act as potent, cytoprotective agents, through modulation of apoptotic pathways.     

Amurensiosides A-K, 11 new pregnane glycosides from the roots of Adonis amurensis

Five new pregnane tetraglycosides, amurensiosides A-E (1-5), two new pregnane hexaglycosides, amurensiosides F (6) and I (9), two new 18-norpregnane hexaglycosides, amurensiosides G (7) and H (8), and two new pregnane octaglycosides, amurensiosides J (10) and K (11), were isolated from the MeOH extract of the roots of Adonis amurensis. The structures of the new compounds were determined on the basis of extensive spectroscopic analysis, including two-dimensional (2D) NMR data, and the results of hydrolytic cleavage. The isolated compounds were evaluated for their cytotoxic activity against HSC-2 human oral squamous cell carcinoma cells.     

Synthesis of regioisomeric 17β-N-phenylpyrazolyl steroid derivatives and their inhibitory effect on 17α-hydroxylase/C17,20-lyase

The reaction of 3β-hydroxy-21-hydroxymethylidenepregn-5-en-3β-ol-20-one (1) with phenylhydrazine (2a) affords two regioisomers, 17β-(1-phenyl-3-pyrazolyl)androst-3-en-3β-ol (5a) and 17β-(1-phenyl-5-pyrazolyl)androst-5-en-3β-ol (6a). The direction of the ring-closure reactions of 1 with p-substituted phenylhydrazines (2b-e) depends strongly on the electronic features of the substituents. Oppenauer oxidation of 3β-hydroxy-17β-exo-heterocyclic steroids 5a-e and 6a-e yielded the corresponding Δ⁴-3-ketosteroids 9a-e and 10a-e. The inhibitory effects (IC₅₀) of these compounds on rat testicular C_17,20-lyase were investigated by means of an in vitro radioligand incubation technique.     

Furostanol saponins from the rhizomes of Dioscorea japonica and their effects on NGF induction

The rhizome of Dioscorea japonica is a food and medicinal source known as ‘San Yak’ in Korea. Two new furostanol saponins, coreajaponins A (1) and B (2), together with 10 known compounds (3-12) were isolated from the rhizomes of D. japonica. Their structures were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and chemical methods. Nerve growth factor (NGF), a crucial factor for neuronal survival and differentiation, can potentially improve neurodegenerative diseases and diabetic polyneuropathy. We evaluated the effects of isolates (1-12) on NGF induction in a C6 rat glioma cell line. Coreajaponin B (2) upregulated NGF content without significant cell toxicity, as did 6, 8, 9, and 11.     

Syntheses, structures, and mesomorphic properties of two series of oxovanadium(IV) salen and salpn complexes with 4-substituted long alkoxy chains

Two series of oxovanadium(IV) salen and salpn complexes containing 4-substituted alkoxy chains of aromatic rings, [VO((4-C_nH_2n+1O)₂salen)] (n = 3 (1), 4 (2), 6 (3), 8 (4), 10 (5), 12 (6), 14 (7), 16 (8), 18 (9), and 20 (10) and salen = N,N′-ethylenebis(salicylideneiminato)), and [VO((4-C_nH_2n+1O)₂salpn)] (n = 8 (11), 10 (12), 12 (13), 14 (14), 16 (15), and 18 (16) and salpn = N,N′-propylenebis(salicylideneiminato)), have been prepared and their mesomorphic properties have been investigated. The crystal structures of 1-9 except for 7 by an X-ray crystallographic analysis have been revealed. Complexes 4-9 in the solid state have been confirmed as novel bilayer crystal structures composed of only the VO(IV) complex without linear chains via the VO units. The VO(IV) complexes with longer alkoxy chains of 8-10 transferred from the bilayer crystal to the bilayer metallomesogens (liquid crystals). Based on the X-ray analyses and the precise extinction rules for 8-10 with the bilayer metallomesogens, complexes 8-10 were identified as the liquid crystalline (M(Pa2₁)) phase derived from 80 layer groups. On the other hand, the 4-alkoxysalpn complexes of 14-16 showed the unusual rectangular columnar mesophase (Col_r) with the linear chain via the VO units supported by the existence of the VO stretching band characteristic of weak linear chain formation via the VO units in the liquid crystal.     

Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.     

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, structure and theoretical studies of Hg(II)-NH carbene complex of annulated ligand pyridinyl[1,2-a]{2-pyridylimidazol}-3-ylidene hexaflurophosphate

Experimental and theoretical studies of a new class of novel annulated imidazolium scffords 2a, 2b, 2c and their Hg(II)-NHC complexes 3a, 3b and 3c have been synthesized and characterized by different spectroscopic techniques. Molecular structures of 3a and 3b have been determined by single crystal X-ray diffraction studies. Virtual linear geometry [C_carbene-Hg-C_carbene 176.56(17)°] around Hg of the complex 3b is observed where as in 3a and 3c its deviate a more. DFT calculations provide geometrical parameters in conformity with the experimental values in case of 3a. The molecules prefer syn configuration over the anti due to lower energy supported by theoretical studies. Attention has given paid for theoretical calculations and comparison of 3a and 3c to observe the steric effect of -CH₃ group in the scaffords where as in case of 3b the -CH₃ group remain innocent.     

Inhibition of P-glycoprotein-mediated Multidrug Resistance (MDR) by N,N-bis(cyclohexanol)amine aryl esters: further restriction of molecular flexibility maintains high potency and efficacy

Conformational modulation of the aryl portion of a set of N,N-bis(cyclohexanol)amine aryl esters (1a-d) that are potent Pgp-dependent MDR inhibitors has been performed. Toward this end the trans-3-(3,4,5-trimethoxyphenyl)acrylic acid present in set 1 was substituted with 3-(3,4,5-trimethoxyphenyl)propanoic and 3-(3,4,5-trimethoxyphenyl)propiolic moieties to give sets 2 and 3, respectively. While the introduction of 3-(3,4,5-trimethoxyphenyl)propanoic moiety resulted in a definite drop in potency and efficacy, esterification with 3-(3,4,5-trimethoxyphenyl)propiolic acid gave four isomers (3a-d) that maintain high potency and possess optimal efficacy. These results are discussed in terms of conformational flexibility of the different sets of compounds.     

(Pyrazolylmethyl)pyridine platinum(II) and gold(III) complexes: Synthesis, structures and evaluation as anticancer agents

Reactions of 2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L1), 2-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L2), 2-(3,5-di-tert-butylpyrazol-1-ylmethyl)pyridine (L3) and 2-(3-p-tolylpyrazol-1-ylmethyl)pyridine (L4) with K₂[PtCl₄] in a mixture of ethanol and water formed the dichloro platinum complexes [PtCl₂(L1)] (1), [PtCl₂(L2)] (2), [PtCl₂(L3)] (3) and [PtCl₂(L4)] (4). Complex 1, [PtCl₂(L1)], could also be prepared in a mixture of acetone and water. Performing the reactions of L2 and L3 in a mixture of acetone and water, however, led to C-H activation of acetone under mild conditions to form the neutral acetonyl complexes [Pt(CH₂COCH₃)Cl(L2)] (2a) and [Pt(CH₂COCH₃)Cl(L3)] (3a). The same ligands reacted with HAuCl₄ · 4H₂O in a mixture of ethanol and water to form the gold salts [AuCl₂(L1)][AuCl₄] (5) [AuCl₂(L2)][Cl] (6) [AuCl₂(L3)][Cl] (7) and [AuCl₂(L4)][AuCl₄] (8); however, with the pyrazolyl unit in the para position of the pyridinyl ring in 4-(3,5-dimethylpyrazol-1-ylmethyl)pyridine (L5), 4-(3,5-diphenylpyrazol-1-ylmethyl)pyridine (L6) neutral gold complexes [AuCl₃(L5)] (9) and [AuCl₂(L6)] (10) were formed; signifying the role the position of the pyrazolyl group plays in product formation in the gold reactions. X-ray crystallographic structural determination of L6, 2, 33a, 8 and 10 were very important in confirming the structures of these compounds; particularly for 3a and 8 where the presence of the acetonyl group confirmed C-H activation and for 8 where the counter ion is . Cytotoxicity studies of L2, L4 and complexes 1-10 against HeLa cells showed the Au complexes were much less active than the Pt complexes.     

Novel fungicidal benzylsulfanyl-phenylguanidines

A series of substituted benzylsulfanyl-phenylamines was synthesized, of which four substituted benzylsulfanyl-phenylguanidines (665, 666, 667 and 684) showed potent fungicidal activity (minimal fungicidal concentration, MFC ? 10 μM for Candida albicans and Candida glabrata). A benzylsulfanyl-phenyl scaffold with an unsubstituted guanidine resulted in less active compounds (MFC = 50-100 μM), whereas substitution with an unsubstituted amine group resulted in compounds without fungicidal activity. Compounds 665, 666, 667 and 684 also showed activity against single C. albicans biofilms and biofilms consisting of C. albicans and Staphylococcus epidermidis (minimal concentration resulting in 50% eradication of the biofilm, BEC50 ? 121 μM for both biofilm setups). Compounds 665 and 666 combined potent fungicidal (MFC = 5 μM) and bactericidal activity (minimal bactericidal concentration, MBC for S. epidermidis ? 4 μM). In an in vivo Caenorhabditis elegans model, compounds 665 and 667 exhibited less toxicity than 666 and 684. Moreover, addition of those compounds to Candida-infected C. elegans cultures resulted in increased survival of Candida-infected worms, demonstrating their in vivo efficacy in a mini-host model.     

The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation

A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by sequential Bigineli’s reaction, reduction followed by reaction of resulting amines with different arylisocynates. All the synthesized (1-23) compounds were screened against the pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation study reveled that among all the compounds screened, compounds 12 and 17 found to have promising anti-inflammatory activity (68-62% TNF-α and 92-86% IL-6 inhibitory activity at 10 μM). Interestingly compounds 3, 4, 5, 6, 15, 22 and 23 revealed promising antimicrobial activity at MIC of 10-30 μg/mL against selected pathogenic bacteria and fungi.     

Palladium(II), platinum(II), ruthenium(II) and mercury(II) complexes of potentially tridentate Schiff base ligands of (E, N, O) type (E = S, Se, Te): Synthesis, crystal structures and applications in Heck and Suzuki coupling reactions

Schiff bases of 2-hydroxybenzophenone (HBP) (C₆H₅)(2-HOC₆H₄)CN(CH₂)_nEAr (L1/L2: E = S, Ar = Ph, n = 2/3; L3/L4: E = Se, Ar = Ph, n = 2/3; L5/L6: E = Te, Ar = 4-MeOC₆H₄, n = 2/3) and their complexes [PdCl(L-H)] (L = L1−L6; 1, 2, 3, 5, 7, 11), [PtCl(L3-H/L5-H)] (4/8), [PtCl₂(L4/L6)₂] (6/12), [(p-cymene)RuCl(L5/L6)]Cl (9/13) and [HgBr₂(L5/L6)₂] (10/14) have been synthesized and characterized by proton, carbon-13, selenium-77 and tellurium-125 NMR, IR and mass spectra. Single crystal structures of L1, 1, 3, 4, 5 and 7 were solved. The Pd-E bond distances (Å): 2.2563(6) (E = S), 2.3575(6)−2.392(2) (E = Se); 2.5117(5)−2.5198(5) (E = Te) are near the lower end of the bond length range known for them. The Pt-Se bond length, 2.3470(8) Å, is also closer to the short values reported so far. The Heck and Suzuki reaction were carried out using complexes 1, 3, 5 and 7 as catalysts under aerobic condition. The percentage yields for trans product in Heck reaction were found upto 85%.     

Bioactive polyhydroxylated sterols from the marine sponge Haliclona crassiloba

Four new polyhydroxylated sterols, named halicrasterols A–D (1–4), together with six known analogs (5–10) were isolated from the marine sponge Haliclona crassiloba. Compounds 1 and 2 represented rare examples of steroids featuring 17(20)E-double bonds. The structures of 1–10 were elucidated by spectroscopic analysis and comparison with reported data. This is the first report of a steroid profile for this species. The antimicrobial activities of 1–10 were evaluated against a panel of bacterial and fungal strains in vitro, and compounds 4 and 9 showed moderate activity against some of the Gram-positive strains with MICs ranging from 4 to 32 μg/mL.     

Ecdysteroids and a sucrose phenylpropanoid ester from Froelichia floridana

Phytoecdysteroid glycosides (1-5) and a phenylpropanoid ester of sucrose (6) were isolated from the whole plant of Froelichia floridana, along with eight known compounds including three ecdysteroids (7-9), four flavonoids (10-13), and one phenolic compound (14). Structures were determined using a combination of spectroscopic techniques. Compounds 1, 2 and 6-14 were tested in vitro for their activity against human DNA topoisomerase I. Compound 13 (diosmetin) showed marginal inhibition against topoisomerase I with IC₅₀ of 130 μM in conjunction with low intercalation ability.     

Synthesis and antimicrobial activity of some new N-glycosides of 2-thioxo-4-thiazolidinone derivatives

5-Arylidene-2-thioxo-4-thiazolidinones 3a-f react with each of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl and α-d-galactopyranosyl bromides 4a,b in acetone in the presence of aqueous potassium hydroxide at room temperature to afford N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) or N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl) 2-thioxo-4-thiazolidinone derivatives 5a-f. Similarly, the reaction of 5-cycloalkylidene-2-thioxo-4-thiazolidinones 7a,b with 4a gave the corresponding N-glucosides 8a,b. Also, 5-pyrazolidene rhodanines 10a-e react with 4a to afford the new N-glucosides 11a-e. Treatment of compounds 15 and 16 with 4a in the presence of few drops of triethylamine or in KOH solution accomplished the mono- and bis-nucleosides 17 and 18, respectively. Some selected products were tested for their antimicrobial activities.