Dinuclear silver(I) complexes of 24-membered bibracchial tetraimine Schiff base macrocycles derived from 2,5-diformylthiophene

The cyclocondensation of 2,5-diformylthiophene and the amines N,N-bis-(2-aminoethyl)-2-phenylethylamine, N,N-bis-(2aminoethyl)-t-butyl-amine and N,N-bis-(2-aminoethyl)-t-butyl-amine in the presence of silver(I) salts yields homodinuclear bibracchial tetraimine Schiff base macrocyclic complexes. The structures of two such complexes are also reported. The complex Ag₂L⁴(NO₃)(PF₆) (2) crystallises in the triclinic space group , No. 2) and has unit-cell dimensions a = 12.834(6), B = 13.183(6), C = 14.588(7) Å, = 64.86(4), β = 79.77(4), γ = 69.44(3)° with Z = 2; there is a monodentate and singly bridging nitrate anion present and the Ag---Ag separation is 4.161 Å. The complex Ag₂L⁴(CH₃CN)₂(BF₄)₂·CH₃CN (9) crystallises in the triclinic space group , No. 2) and has unit-cell dimensions a = 9.297(4), B = 12.985(3), C = 21.770(5) Å, = 91.570(10), β = 92.33(3), γ = 97.92(3) ° with Z = 2; there is a strongly bonded acetonitrile molecule coordinated to each silver atom and the Ag---Ag separation is 4.920 Å.     

Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines

Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K_i = 5.9 nM; 11d: K_i = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K_i = 5.9 nM; 11c: K_i = 6.0; 12c: K_i = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ₂ affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ₁ and σ₂ receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5–2-fold) as well as for bromo derivative 18c (≈3-fold).     

Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC₅₀ = 6.13 μM) is significantly higher than kojic acid (IC₅₀ = 33.3 μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.     

5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines as dual inhibitors of Mycobacterium tuberculosis and influenza virus: Synthesis and evaluation

This study describes synthesis and evaluation of novel 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines 7a-o as dual inhibitors of Mycobacterium tuberculosis and influenza virus. Huisgen’s [3+2] dipolar cycloaddition of 6-(azidomethyl)-5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline 5 with various alkynes 6a-o using sodium ascorbate and copper sulphate gave new dihydroquinoline-1,2,3-triazoles 7a-o in good to excellent yields. The new compounds were evaluated for in vitro antimycobacterial against M. tuberculosis H37Rv (Mtb) and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). Among the fifteen new analogs, compounds 7a (MIC: 3.12 µg/mL), 7j and 7k (MIC: 6.25 µg/mL) were identified as potent antitubercular agents. The virus-inhibiting activity of all the fifteen compounds was found to be moderate, and among them the compound 7l, bearing thiophene moiety appeared the most active with good selectivity index (IC₅₀ = 19.5 µg/mL; SI = 15). The results presented here will help developing newer dual inhibitors of tuberculosis and influenza virus.     

Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100 mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.     

Synthesis and in vitro antimicrobial activities of new (cyano-NNO-azoxy)pyrazole derivatives

The antibacterial and antifungal activity of a series of products, in which the 1,5-dimethyl-4-(cyano-NNO-azoxy)pyrazol-3-yl and 1,3-dimethyl-4-(cyano-NNO-azoxy)pyrazol-5-yl moieties were linked to pyridine, pyrazole, isoxazole, thiophene and the furan ring, were examined. No molecule displayed activity against the Gram-negative bacteria tested. Conversely, some compounds displayed activity against two Staphylococcus aureus strains, including the methicillin resistant strain. All compounds displayed interesting antifungal activity, the most active compound of the series being the thiophene derivative 7a. This compound’s activity against Candidakrusei and Candidaglabrata (MIC = 0.25 and 0.5 μg/mL, respectively), two fungal species resistant to azoles, is noteworthy. The presence of the cyano function appeared essential for activity.     

Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5-(hetero)arylethynyl thiophene derivatives

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G₂/M and sub-G₁ phases of the cell cycle.     

Two new compounds with antimicrobial activities from the seeds of Voacanga africana

Two new compounds, (R)-4-(2-methylpentyl)-4H-dithieno[2,3-b:3′,2′-e]pyran (1) and 4-(2-ethylbutyl)-4H-dithieno[2,3-b:3′,2′-e]pyran (2) were extracted from the seeds of Voacanga africana. The molecular structures of these compounds were measured with the help of broad spectroscopic (1D and 2D-NMR, IR, ESI-TOF-MS, HR-MS) analyses. The primary pharmacological operations of these compounds were brought to evaluation by applying the antibacterial extrasomatic test. The results revealed that compound 1 and 2 were in an effective position to stop the growth of Escherichia coli, Streptococcus and Salmonella typhi. On the other hand, the inhibitory impacts on Staphylococcus aureus as well as Pseudomonas aeruginosa were not apparent.