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).     

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.     

Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception

We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60 s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 μg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 μg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.     

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, 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.     

2-(1-(Dimethylamino)ethyl)phenylpalladium(II) complexes 5-functionalized with fluorous silyl tails

New fluorous-organometallics based on the chiral ligand α-methyl-N,N-dimethylbenzylamine (TMBA) were prepared by treatment of fluorous silyl bromide reagents with in situ 4-lithiated TMBA to give fluorous N,N-dimethyl(α-methyl-4-trialkylsilylbenzyl)amine ligands 1a-1c that vary in the number of fluorous tails attached to the Si atom. Ligands 1a-1c were successfully cyclo-palladated by treatment with Pd(OAc)₂/LiCl in methanol to furnish the corresponding chloride-bridged dimeric arylpalladium(II) complexes 2a-2c in good yields. The latter derivatives could be converted into monomeric Lewis-base adducts by complexation with pyridine (3a-3c), or triphenylphosphine (4a-4c). The crystal structure of triphenylphosphine complex 4a has been elucidated. To probe their fluorophilicity, the partition coefficient of each of the derivatives in the fluorous biphasic solvent (FBS) system perfluoromethylcyclohexane/n-octane has been determined.     

Synthesis, structures and ligating properties of 2,6-bis(phosphino)thiophenol derivatives

New t-butyl-aryl thioethers where the aryl group is 2,6-bis(phosphino)phenyl have been synthesized. The syntheses were completed via sequential ortho-lithiations of t-butylphenylsulfide, followed by chlorophosphine (ClPR₂) quenches; symmetric (2,6-bis(diphenylphosphino)phenyl, (4a)) and unsymmetric (2-diisopropylphosphino-6-diphenylphosphino)phenyl, (4b) aryl groups were obtained. Treatment of 4a with Li or Na naphthalenide yielded 2,6-bis(diphenylphosphino)thiophenol 5. Reactions of 4a or 5 with NiCl₂ · 6H₂O yielded nickel bis(phosphinothiophenolate) 6. Compounds 4a,b, 5 and 6 were characterized by ¹H and ³¹P NMR, and by mass-spectrometry. In addition, 4a, 5 and 6 were characterized by single crystal X-ray diffraction methods.     

5-(2'-Pyridyl)-2-aminothiazoles: alkyl amino sulfonamides and sulfamides as potent NPY(5) antagonists

Synthesis, SAR and physico-chemical properties of an alkyl aminothiazole series 8 and 16 are described. 2-Pyridylaminothiazole based compounds such as 8c and 16a exhibit high affinity at the NPY₅ receptor with desirable c Log Ps and solubilities. However, they also suffer from high in vitro and in vivo clearance. Compound 16a partially inhibits the feeding behavior elicited by i.c.v. injection of the selective NPY₅ agonist [cPP^1-7, NPY^19-23, Ala³¹, Aib³², Gln³⁴]-human pancreatic polypeptide polypeptide (cPP).     

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.     

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).     

Discovery of novel xanthone derivatives as xanthine oxidase inhibitors

Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. In this study, a series of xanthone derivatives were synthesized as effective and a new class of xanthine oxidase inhibitor. Compounds 8a, 8c, 8i, 8g and 8r showed good inhibition against xanthine oxidase. The presence of a cyano group at the para position of benzyl moiety turned out to be the preferred substitution pattern. Molecular modeling studies were performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors associated with the xanthone framework.     

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.     

Solid-gas carbonylation of aryloxide rhodium(I) complexes: stepwise reaction forming Vaska-type complexes

Aryloxide rhodium(I) complexes Rh(OAr)(PPh₃)₃ (1a: Ar=C₆Cl₅, 1b: Ar=C₆F₅, 1c: Ar=C₆H₄-NO₂-4) react with CO in toluene solutions to produce Vaska-type complexes trans-Rh(OAr)(CO)(PPh₃)₂ (2a: Ar=C₆Cl₅, 2b: Ar=C₆F₅, 2c: Ar=C₆H₄-NO₂-4). Carbonylation of a similar complex with PMe₃ ligands, Rh(OC₆H₄-NO₂-4)(PMe₃)₃ (3c), also forms trans-Rh(OC₆H₄-NO₂-4)(CO)(PMe₃)₂ (4c). Molecular structures of the complexes are determined by X-ray crystallography and NMR spectroscopy. Complex 1a reacts with CO in the absence of solvent to produce a mixture of 2a and complex A, the latter of which shows the IR and ¹³C{¹H} signals due to the carbonyl ligand at different positions from those of 2a. Addition of Et₂O to the above mixture turns it into analytically pure 2a. Carbonylation of 1b and 1c under the solvent-free conditions produces complexes B and C as the respective products of the solid-gas reaction. Recrystallization of B and C turns them into 2b and 2c, respectively. Complex 3c also reacts with CO in the solid state to form a mixture of 4c and complex D, although the latter complex is converted slowly into 4c even in the solid state.     

Intramolecular ether oxygen coordination in the zinc complexes with dipicolylamine (DPA)-derived ligands

The ether oxygen coordination to the zinc center in the complexes with dipicolylamine (DPA)-derived ligands, N-(2-methoxyethyl)-N,N-bis(2-pyridylmethyl)amine (L), N-(3-methoxypropyl)-N,N-bis(2-pyridylmethyl)amine (L′), and N-{3-(2-pyridylmethyloxy)propyl}-N,N-bis(2-pyridylmethyl)amine (L^Py) has been discussed. Upon chelation of the oxygen atom, L forms a five-membered chelate ring with respect to the 2-aminoethyl ether moiety whereas L′ forms a six-membered chelate in 3-aminopropyl ether unit. This difference was highlighted by the crystal structures of ZnCl₂ complexes, in which [Zn(L)Cl₂] (1) exhibited ether oxygen coordination but [Zn(L′)Cl₂] (2) had the ether oxygen non-coordinated. The terminal pyridyl group of L^Py facilitates the ether oxygen atom coordination via a metal binding from the basal plane trans to the aliphatic nitrogen.     

Ionic liquid promoted synthesis, antibacterial and in vitro antiproliferative activity of novel α-aminophosphonate derivatives

Ionic liquid ethyl ammonium nitrate is used as an excellent catalyst and solvent for three-component one-pot reaction of an aldehydes, amines and diethylphosphite to form novel α-aminophosphonates at room temperature. Among the various catalysts, the preparation of ethyl ammonium nitrate is an environmental friendly, cost effective and recyclable catalyst. Compounds 4b, 4c, 4d, 4f and 4j were found more potent antibacterials against pathogenic microorganisms. Whereas, compounds 4a, 4g, 4h and 4j inhibits growth of active Escherichia coli NCIM 2645 and Salmonella typhi NCIM 2501. Compound 4j was found a promising antiproliferative agent against A549 and SK-MEL2 human melanoma cell lines.     

An investigation of Cu(II) and Ni(II)-catalysed hydrolysis of (di)imines

The reactions of six diimine ligands with Cu(II) and Ni(II) halide salts have been investigated. The diimine ligands were Ph₂CN(CH₂)_nNCPh₂ (n = 2 (Bz₂en, 1a), 3 (Bz₂pn, 1b), 4 (Bz₂bn, 1c)), N,N′-bis-(2-tert-butylthio-1-ylmethylenebenzene)-2,2′diamino-biphenyl (2), N,N′-bis-(2-chloro-1-ylmethylenebenzene)-1,3-diaminobenzene (3) and N,N′-bis-(2-chloro-1-ylmethylenebenzene)-1,2-ethanediamine (4). Reactions of 1a-c, 2-4 with CuCl₂·2H₂O in dry ethanol at ambient temperature led to complete or partial hydrolysis of the diimine ligands to ultimately form copper diamine complexes. The non-hydrolyzed complexes of 1b and 1c, [Cu(L)Cl₂] (L = 1b, 1c), could be isolated when the reactions were carried out at low temperatures, and the half-hydrolyzed complex [Cu(Bzpn)Cl₂] could also be identified via X-ray crystallography. Similarly, reactions of 1a or 1b with NiCl₂·6H₂O or [NiBr₂(dme)] led to rapid hydrolysis of the imines and Ni complexes containing half-hydrolyzed 1a (Bzen; [trans-[Ni(Bzen)₂Br₂]) and 1b (Bzpn; [Ni(Bzpn)Br₂] could be isolated and identified via single crystal X-ray analysis. Kinetic studies were made of the hydrolyses of 1a, 1b in THF and 2 in acetone, in the presence of Cu(II), and of 1a in acetonitrile, in the presence of Ni(II). Activation parameters were determined for the latter reaction and for the copper-catalyzed hydrolysis of 2; the relatively large negative activation entropies clearly indicate rate-determining steps of an associative nature.     

Syntheses and structures of Ag(I) compounds containing btp ligands

Four new Ag(I) complexes with three different modes of structures were obtained by varying the counteranions , and their structures characterized by single-crystal X-ray diffraction analysis. Compounds 1, 2, and 3 crystalize in the C-centered monoclinic space group C2/m. Compound 4 crystalizes in the monoclinic space group P2₁/c. The crystal structures of these complexes show that the complexes 1, 2, and 3 form ligand-supported dinuclear rings, and the dinuclear units of 1 and 3 are further linked by anions to form one-dimensional polymer, while the complex 4 forms an one-dimensional zigzag chain. The structural differences between 1, 2, 3, and 4 show the influences of the counteranions on the structures of the complexes.     

Synthesis and structural characterizations of para-bis(dialkyl/diarylphosphino)phenylenes built around tetrahalogenated benzene cores

Double deprotonation of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene by lithium diisopropylamide (LDA) in ethereal solutions is facile at very low temperatures (T < −90 °C). The organo-dilithium intermediates thus generated react readily with chlorophosphines ClPR₂ (R = Ph and/or ⁱPr), producing 1,2-dibromo-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1a), 1,2-dibromo-3,6-bis(diisopropylphosphino)-4,5-difluorobenzene (1b) and 1-bromo-2-chloro-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1c). Corresponding P-oxides 2a-c are obtained by oxidation of 1a-c with H₂O₂. Analogous reactions of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene with only 1 equiv. of LDA do not result in selective monodeprotonations, as 1a and 1c are formed preferentially after ClPPh₂ quench. All of the isolated new compounds were fully characterized by multinuclear NMR spectroscopy, elemental analysis and/or mass-spectrometry. In addition, 1a, 1c, 2a, and 2b were characterized by single crystal X-ray diffraction methods.     

Synthesis and antimicrobial evaluation of bile acid tridentate conjugates

Two series of novel bile acid tridentate conjugates with different linkers were synthesized and characterized, and their biological activities in vitro were evaluated. The procedure was straightforward and efficient to be carried out with high overall yield. The antimicrobial activity of the synthesized compounds against Saccharomyces cerevisiae, Aspergillus niger, Escherichia coli and Staphylococcus aureus was investigated in vitro. The best activity of minimal inhibitory concentrations (MICs) for 1c, 1c′, 2c and 2c′ against S. cerevisiae was up to 0.125 μg/mL.     

Discovery of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides active against efflux-mediated resistant Streptococcus pneumoniae

A series of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides, were discovered, structurally characterized and biologically evaluated. They have shown good antibacterial activity against selected Gram-positive and Gram-negative bacterial strains. These include N″ substituted 9a-(N′-carbamoyl-γ-aminopropyl)- (6a,c), 9a-(N′-thiocarbamoyl-γ-aminopropyl)- (7a,e), 9a-[N′-(β-cyanoethyl)-N′-(carbamoyl-γ-aminopropyl)]- (9a-c, 9g) 9a-[N′-(β-cyanoethyl)-N′-(thiocarbamoyl-γ-aminopropyl)]-derivatives (10d-f) of 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3).Among the synthesized compounds thiourea 7a and urea 9b have shown substantially improved activity comparable to azithromycin (1) and significantly better activity than the 3-decladinosyl-azithromycin (2) and the parent 3-cladinosyl analogues against efflux-mediated resistant S. pneumoniae.