Oxa-Pictet–Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ₁ affinity (K_i 20–26 nM) and σ₁/σ₂ selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ₁ affinity and σ₁/σ₂ selectivity.     

Anti-influenza active and low toxic N-phenyl-substituted β-amidoamidines structurally related to natural antibiotic amidinomycin

A set of racemic N-phenyl-substituted β-amidoamidines hydrochlorides 4, which are structurally related to natural antiviral agent amidinomycin (1), was synthesized in four steps starting from methacryloyl anilide (5). In the final step of the synthetic route, an uncommon monoacylation of β-aminoamidine 8 at the less reactive β-phenylamino-group took place. To rationalize this result, a mechanism which involves initial acylation at the more active amidine-function followed by intramolecular acyl-group transfer to β-phenylamino-group was suggested. All three β-amidoamidines 4d–f bearing long linear aliphatic chain (from n-C₈H₁₇ to n-C₁₂H₂₅) revealed significant in vitro activity against influenza A virus (H3N2) and modest cytotoxicity. The in vitro antiviral potency of 4d,e is 6–20 times greater than that of commercial rimantadine with lower EC₅₀ values and higher therapeutic index. The non-toxic in vivo compounds 4d–f showed a beneficial protective effect in influenza A (H3N2) infected mice.     

Computational investigation of the geometric structures of [(CN)5PtTl(CN)n]n− (n=0, 1, 2 or 3)

[(CN)₅PtTl(CN)_n]ⁿ⁻ (n=0–3, complexes I–IV) have been studied computationally using quasi-relativistic gradient-corrected density functional theory. Good agreement is obtained with previous EXAFS and Raman data for complexes II–IV, but calculations significantly overestimate the PtTl bond length and underestimate ν(PtTl) for complex I. The addition of co-ordinating water molecules to the thallium atom in complexes I–III has little effect on complexes II and III, but significantly shortens the PtTl bond in complex I, bringing it into excellent agreement with experiment. The bond length shortening is traced to intramolecular hydrogen bonding. The total molecular bonding energies of hydrated I and I′ (in which the axial ligands on the thallium and platinum atoms are interchanged) are found to be very similar to one another, suggesting that complex I might exist as a mixture of isomers in solution.     

The structure and reactivity towards oxygen transfer of pyrazinedicarboxylato peroxo titanium derivatives. Molecular and crystal structure of peroxo(pyrazine 2-carboxylato 3-carboxyl)(acetylacetonato)(hexamethylphosphortriamide) titanium(IV)

The synthesis and properties, with respect to oxygen transfer to olefins, of four peroxo Ti(IV) complexes of pyrazine- and pyridinedicarboxylic acids, are reported. The X-ray structure of Ti- [pz(COO)(COOH)](acac)(HMPA), 1, was performed; it essentially revealed that the pyrazine ligands are non-bridging: the carboxylate group at the 2 position is deprotonated while the other carboxylate forms intramolecular hydrogen bonds. Strong stabilization of the peroxo moiety precluded oxygen transfer from 1 to organic substrates. On the other hand, pyrazine- and pyridine-2,5-dicarboxylic acids yielded polymeric compounds 2–4 where both carboxylate groups of the ligands are deprotonated. Complexes 2–4 epoxidize tetramethylethylene; the reactivity thus revealed is attributed to the breaking of the pyrazine or pyridine bridges in solution, which liberates a vacant site on the metal. Crystal data for 1: C₂₃H₄₆N₈O₁₀P₂Ti₂, triclinic, a = 16.295(6), b = 15.247(6), c = 15.398(6) Å, a = 90.36(2)°, β= 115.50(2)°, γ = 89.21(2)°; space group P1, Z = 4.     

Synthesis and properties of (2-pyridyl)alkylamine- and (2-pyridyl)alkylamine–amide-coordinated copper(II) complexes: Structures and non-covalent interactions

Reaction of the ligand N-methyl-N-((6-pivaloylamido-2-pyridyl)methyl)-N-(2-pyridylethyl)amine (mpppa) with equimolar amounts of [Cu(H₂O)₆][ClO₄]₂ or CuCl₂ · 2H₂O in MeCN afforded mononuclear copper(II) complexes [Cu(mpppa)][ClO₄]₂ (1) and [Cu(mpppa)Cl₂] (2). Crystal structure analysis reveals CuN₃O (two pyridyl, an aliphatic amine, and an amide oxygen) coordination in 1 and CuN₃Cl₂ (two pyridyl, an aliphatic amine, and two chlorides) coordination in 2. Crystal packing diagram of 1 reveals that one of the perchlorate counteranions provides weak coordination to copper(II) centers and in turn the copper(II) centers assume pseudo-six-coordination, generating 1D chain. Notably, one of the copper(II)-coordinated chloride ions in 2 participates in an intramolecular N–H?Cl interaction. Intermolecular C–H?Cl interactions in the solid state generate helical structure. Spectroscopic (IR, UV–Vis, and EPR) and redox properties of the two complexes have been investigated and compared.     

Characterization of bio-related vanadium and zinc complexes containing tetradentate dithiolate-disulfide, -diamine and -amine-amide ligands

The reaction of [VCl₃(PMe₂Ph)₃] _{with HSS′S′SH (where the HS are thiophenolate and the S′ thioether functions, respectively), H2–1, yields [VCl(μ-SS′S′S)]2 (3) with one of the thiolate groups of each of the two ligands in the bridging mode. Reaction of Na2–1 with [VOCl2(thf)2] leads to a polymeric product of composition [VO(SS′S′S)]x (4). The products obtained from the reaction between [VOCl2(thf)2] and NaSNNSNa, Na2–2, (S is thiophenolate, N the amine function) depend on subtle changes in the diamine backbone of this ligand: If the amine functions are linked by -CH2CH2– (2a), the tetranuclear V^IV complex [V(SNNS)μ-O]4 (5) is formed alongside the V^III complex [VCl(SNNS)]. If the backbone is -CH(Me)CH(Me)- (2b), [VO(SNNS)] (7) and the dinuclear, asymmetrically oxo-bridged V^IV complex [{(SNN ^– S)(thf)V}μ-O{V(SNN ^– S)}] (8) are obtained. In 8, one amine of each of the two ligands is deprotonated to the amide group. In either case, the complexation is accompanied by oxidation of the thiolates to disulfides, leading to the generation of teraazatetrathio-cycloeicosanes (6a/b). Compounds 5 and 8·2THF have been structurally characterized by X-ray analyses. The connectivities have further been established for 3·2CH2Cl2 and for 6b, which exhibits the same conformation as formally characterized 6a. The cluster compound 5 is stabilized by an extended intramolecular N-H...O and N-H...S) hydrogen-bonding network. In 7·2THF, one of the THFs of crystallization is hydrogen-bonded to the NH of the penta-coordinated {VO(SNN ^– S)} moiety; further, there is an intramolecular hydrogen bond between one of the thiolates of this tetragonal-pyramidal half of the molecule and the NH of the octahedral {VO(SNN ^– S)thf} half. The generation of the ligand 2b from its precursor compound, the zinc complex [Zn(SNNS)] (9) leads to the structural characterization of 9·CH3OH with a large SZnS bite angle and a strong hydrogen bond between the methanolic OH and one of the thiolate sulfurs. The relevance of these compounds in biological systems is discussed.}     

Synthesis and bioevaluation of 6-chloropyridazin-3-yl hydrazones and 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines as cytotoxic agents

An efficient synthesis of a series of 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines is described via intramolecular oxidative cyclization of various 6-chloropyridazin-3-yl hydrazones with iodobenzene diacetate. The structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, NMR (¹H and ¹³C) and mass spectral data. All the thirty three compounds 3a-q and 4b-q synthesized in the present study were evaluated for their in vitro cytotoxic activities against two Acute Lymphoblastic Leukemia (ALL) cell lines named, SB-ALL and NALM-6, and a human breast adenocarcinoma cell lines (MCF-7). The results revealed that triazoles 4 exhibit better cytotoxicity than their hydrazone precursors 3. Among triazoles, compounds 4f, 4j and 4q exhibited potent cytotoxic activity against SB-ALL and NALM-6 with IC₅₀ values in the range of ∼1.64–5.66 μM and ∼1.14–3.7 μM, respectively, compared with doxorubicin (IC₅₀ = 0.167 μM, SB-ALL). Compounds 4f, 4j and 4q were subjected to apoptosis assay after 48 h treatment and these compounds induced apoptosis of NALM-6 cells via caspase 3/7 activation. Results revealed that compound 4q represents potential promising lead.     

Synthesis,X-ray crystal structure study and antitumoral evaluations of 5,6-disubstituted pyrimidine derivatives

5,6-Disubstituted pyrimidine derivatives (3–20) were prepared by intramolecular cyclization reaction of α-(1-carbamyliminomethylene)-γ-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by ¹H NMR, ¹³C NMR and mass spectra. Structures of compounds 4, 7 and 14 were unambiguously confirmed by X-ray crystal structural analysis. Supramolecular structures of these three compounds differ significantly. Two N–H?O and one C–H?O hydrogen bonds in 4 form three-dimensional network. One O–H?N hydrogen bond and one π?π interaction self-assemble the molecules of 7 into sheets. In supramolecular aggregation of 14, only π?π stacking interactions participate, so forming chains. The compounds were evaluated for their cytostatic activities against human malignant cell lines. Of all tested compounds, 2,4-dimethoxy-5-methoxytritylethylpyrimidine (9) and 2,4-dichloro-5-chloroethylpyrimidine (14) exhibited the most prominent inhibitory effects. Furthermore, compound 14 showed marked activity against human colon carcinoma (IC₅₀ = 0.4 μM).     

Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials

The 4-(heteroarylthio)thieno[2,3-d]pyrimidine (TTP) series of antimalarials, represented by 1 and 17, potently inhibit proliferation of the 3D7 strain of P. falciparum (EC₅₀ 70–100 nM), but suffer from oxidative metabolism. The 1,1-cyclopropylidene isosteres 6 and 16 were designed to obviate this drawback. They were prepared by a short route that features a combined Peterson methylenation / cyclopropanation transformation of, e. g., ketone 7. Isosteres 6 and 16 possess significantly attenuated antimalarial potency relative to parents 1 and 17. This outcome can be rationalized based on the increased out-of-plane steric demands of the latter two. In support of this hypothesis, the relatively flat ketone 7 retains some of the potency of 1, even though it appears to be a comparatively inferior mimic with respect to electronics and bond lengths and angles. We also demonstrate crystallographically and computationally an apparent increase in the strength of the intramolecular sulfur hole interaction of 1 upon protonation.     

Cell attachment to a substratum and cell surface proteases.

The polytripeptide (Tyr-Ala-Glu)_n, n～-175, has been reported to undergo an α-helix-disordered chain transition in aqueous medium (Ramachandran, J., et al. (1971) Biopolymers, 10, 1829–1851). We find from circular dichroism and infrared spectroscopy that, upon transferring (Tyr-Ala-Glu)₉ from aqueous buffer at neutral pH to dioxane-containing media at acidic pH, and in certain other circumstances, a transition from the disordered state to the antiparallel β structure occurs. Molecular weight studies and the independence of the transition from concentration suggest that the β structure is intramolecular. (Tyr-Ala-Glu)₄ shows no evidence for the occurrence of any conformational change under similar conditions.     

Design,synthesis and photoinduced DNA cleavage studies of [1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones

An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λ_max 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O₂⁻) as the major reactive oxygen species responsible for photocleavage process.     

Synthesis and thermal chemistry of isolevoglucosenone

Isolevoglucosenone (1,6-anhydro-2,3-dideoxy-β-d-glycero-hex-2-enopyranos-4-ulose, 3) has been synthesized from levoglucosenone (2) in six steps. Thus, 1,6-anhydro-4-O-benzyl-3-deoxy-β-d-erythro-hexopyranos-2-ulose, obtained by Michael addition of benzyl alcohol to 2, was reduced with sodium borohydride to yield a separable mixture of the C-2 epimeric alcohols 1,6-anhydro-4-O-benzyl-3-deoxy-β-d-arabino- and -ribo-hexopyranose, both of which displayed intramolecular hydrogen-bonding. Acetylation, hydrogenolytic debenzylation, and pyridinium chlorochromate oxidation then led to the 2-O-acetyl-1,6-anhydro-hexos-4-uloses, from which 3 was obtained by tetraethylammonium acetate-catalyzed β-elimination of acetic acid. On sealed-tube thermolysis in the range of 210–260°, 3 generated 3-oxidopyrylium by loss of formaldehyde; this ylide was efficiently trapped by unreacted 3, to yield the [4_π + 2_π]-1,3-dipolar cycloadducts 14 and 15. The structure of 14 was fully elucidated by an X-ray crystallographic study. Neither 3 was, nor the adducts 14 and 15 were, detected among the products from acid-catalyzed pyrolysis of cellulose.     

Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s bases incorporating benzenesulfonamide,methanesulfonamide, and methylsulfonylbenzene scaffolds

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (K_I) in the range 93.5–428.1 nM (AAZ and SLC-0111: K_I, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with K_I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K_I, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with K_I in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K_I, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with K_I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K_I, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.     

Tyrosinase inhibitory study of flavonolignans from the seeds of Silybum marianum (Milk thistle)

Anti-melanogenesis effects of silymarin from milk thistle have been reported recently, but detailed tyrosinase inhibition properties of individual components have not been investigated. This study purported to substantiate tyrosinase inhibition and its mechanism based on a single metabolite. The responsible components for tyrosinase inhibition of target source were found out as flavonolignans which consist of isosilybin A (1), isosilybin B (2), silydianin (3), 2,3-dihydrosilychristin (4), silychristin A (5), silychristin B (6) and silybin (7), respectively. The isolated flavonolignans (1–7) inhibited both monophenolase (IC₅₀ = 1.7–7.6 µM) and diphenolase (IC₅₀ = 12.1–44.9 µM) of tyrosinase significantly. Their inhibitions were 10-fold effective in comparison with their mother skeletons (8–10). Inhibitory functions were also proved by HPLC analysis using N-acetyl-l-tyrosine as substrate. The predominant formation of E_met·I was confirmed from a long prolongation of lag time and a decrease of the static state activity of the enzyme. All tested compounds had a significant binding affinity to tyrosinase with K_SV values of 0.06–0.27 × 10⁴ L·mol⁻¹, which are well correlated with IC₅₀s. In kinetic study, all flavonolignan (1–7) were mixed type I (K_I < K_IS) inhibitors, whereas their mother skeletons (8–10) were competitive ones. The UPLC-ESI-TOF/MS analysis showed that the isolated inhibitors are the most abundant metabolites in the target plant.     

Synthesis,structure elucidation and in vitro anticancer activities of novel derivatives of diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinate and ethyl (4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetate

The worked out and optimized synthesis routes and remarkable antitumour activities in vitro of novel polynitrogenated derivatives of diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinate (7–10) and ethyl (4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetate (11–16) are presented. Small molecules based on the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold (11–16) were obtained with fairly modest to good overall yields by very facile addition reactions of the nucleophilic centred 1-aryl-2-hydrazonoimidazolidine hydroiodides to diethyl acetylenedicarboxylate (DEAD) in the presence of triethylamine (TEA) and a subsequent cyclocondensation of the putative intermediate chain hydrazones. Heterobicyclic products 12 and 14–16 could also be prepared in high overall yields by an effective intramolecular cyclocondensation of the isolated stable and antiproliferative active heterocyclic hydrazones, namely, diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinates (7–10), performed in refluxing DMF. These intermediates are the first products to be formed in the result of an addition of the nucleophilic reactants, namely, 1-aryl-2-hydrazonoimidazolidines of the 1–6 type, bearing the basic nitrogen atom of the hydrazono moiety (N–NH₂), to the carbon–carbon triple bond of the highly electrophilic alkyne, that is, DEAD. Molecular structures of the synthesized compounds (7–16) in the DMSO-d₆ solutions were verified by ¹H NMR and ¹³C NMR spectral data. These were finally confirmed based on the advanced 2D HMBC and HMQC NMR experiments, which were performed for the two representatives (8 and 11) of the two synthesized sets of the bioactive substances. Among the majority of antiproliferative active molecules, the disclosed herein ethyl [4-oxo-8-(3-chlorophenyl)-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (14) is proposed as a promising lead structure for the design of novel highly selective antitumour agents because of the distinctly marked lower cytotoxicity towards the primary cell line of normal HSF cells and several-fold higher against cancer cells used. A double fluorochrome mix-staining was performed in order to find out about the possible mode of action by which this novel small heterobicycle reveals remarkable antiproliferative effects in vitro. Taking into account the obtained double staining results, this small molecule was identified as capable of inducing significantly higher levels of necrotic cells in human cancer cell lines (T47D and HeLa) than in normal HSF cells. Furthermore, its cytotoxicity against cells was found to be connected to the predominant induction of necrosis over apoptosis.     

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7–12 (series A), N,S-dimethyl-dihydropyrimidines 13–18 (series B), hydrazine derivatives of dihydropyrimidine 19–24 (series C), and tetrazolo dihydropyrimidine derivatives 25–30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B–D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC₅₀ values between 34.7–42.9 and 15.0–26.0 μM, respectively. The structure–activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7–12) and C (19–24) were carried out to determine their modes of inhibition and dissociation constants K_i. Compounds of series A (7–12) and series C (19–24) showed a mixed-type of inhibition with K_i values ranging between 15.76–25.66 and 14.63–29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A–D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.     

Novel 8-(furan-2-yl)-3-substituted thiazolo [5,4-e][1,2,4] triazolo[1,5-c] pyrimidine-2(3H)-thione derivatives as potential adenosine A2A receptor antagonists

Novel thiazolotriazolopyrimidine derivatives (23–33) designed as potential adenosine A_2A receptor (A_2AR) antagonists were synthesized. Molecular docking studies revealed that all compounds (23–33) exhibited strong interaction with A_2AR. The strong interaction of the compounds (23–33) with A_2AR in silico was confirmed by their high binding affinity with human A_2AR stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24–26 demonstrated substantial binding affinity and selectivity for A_2AR as compared to SCH58261, a standard A_2AR antagonist. Decrease in A_2AR-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A_2AR antagonist potential of the compounds 24–26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24–26 further supports their role in the alleviation of PD symptoms.