Design,synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity,cell cycle arrest and apoptotic response

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives (3a₁−3d₆) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a₁ exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a₁ may exert antitumor activity by the up-regulation of Bax, intracellular Ca²⁺ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives were designed and synthesized as antitumor agents under the combination principle. The antitumor activity and mechanisms were then evaluated.     

Synthesis,X-ray crystal structure elucidation and Hirshfeld surface analysis of N-((4-(1H-benzo[d]imidazole-2-yl)phenyl)carbamothioyl)benzamide: investigations for elastase inhibition,antioxidant and DNA binding potentials for biological applications

The interest in the present study pertains to the development of a new compound based upon a benzimidazole thiourea moiety that has unique properties related to elastase inhibition, free radical scavenging activity and its DNA binding ability. The title compound, N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-3-benzoyl thiourea (C₂₁H₁₈N₄O₂SH₂O:TUBC), was synthesized by reacting an acid chloride of benzoic acid with potassium thiocyanate (KSCN) along with the subsequent addition of 4-(1H-benzo[d]imidazol-2-yl)benzenamine via a one-pot three-step procedure. The structure of the resulting benzimidazole based thiourea was confirmed by spectroscopic techniques including FTIR, ¹H-NMR, ¹³C-NMR and single crystal X-ray diffraction and further examined by Hirshfeld surface analysis. TUBC was also investigated by using both in silico methodology including molecular docking for elastase inhibition along with quantum chemical studies and in vitro experimental methodology utilizing elastase inhibition and free radical scavenging assay along with DNA binding experiments. Docking results confirmed that TUBC binding was within the active region of elastase. In comparison to the reference drug oleanolic acid, the low IC₅₀ value of TUBC also indicated its high tendency towards elastase inhibition. TUBC scavenged 80% of DPPH˙ radicals which pointed towards its promising antioxidant activity. TUBC–DNA binding by DFT, docking, UV-visible spectroscopy and viscosity measurements revealed TUBC to be a potential drug candidate that binds spontaneously and reversibly with DNA via a mixed binding mode. All theoretical and experimental findings pointed to TUBC as a potential candidate for a variety of biological applications.

A new compound based upon a benzimidazole thiourea moiety that has unique properties related to elastase inhibition, antioxidant and DNA binding ability has been studied.     

Benzo[d]thiazole-2-thiol bearing 2-oxo-2-substituted-phenylethan-1-yl as potent selective lasB quorum sensing inhibitors of Gram-negative bacteria

Quorum sensing is a well-known term for describing bacterial cell–cell communication. Bacteria use quorum sensing pathways to respond to external factors such as nutrient availability, defense mechanisms, and coordinate host toxic behaviors such as biofilm formation, virulence production, and other pathogenesis. Discovery of novel compounds which inhibit quorum sensing without being antibiotic are currently emerging fields. Herein, the library of fifteen benzo[d]thiazole/quinoline-2-thiol bearing 2-oxo-2-substituted-phenylethan-1-yl compounds was designed, synthesized and evaluated to find novel quorum sensing inhibitors. Firstly, compounds were evaluated for their growth inhibitory activities at high concentrations up to 1000 μg mL⁻¹ toward Pseudomonas aeruginosa. Under our conditions, twelve compounds showed moderate growth inhibitory activities in the concentration tested. To our delight, three compounds 3, 6 and 7 do not affect the growth of the bacteria which were chosen for the evaluation of quorum sensing inhibitor activities. In the LasB system, our compounds 3, 6, 7 showed promising quorum-sensing inhibitors with IC₅₀ of 115.2 μg mL⁻¹, 182.2 μg mL⁻¹ and 45.5 μg mL⁻¹, respectively. In the PqsR system, no activity observed suggesting that the selectivity of the compound toward the LasB system. In addition, 7 showed the moderate anti-biofilm formation of Pseudomonas aeruginosa. Docking studies revealed that 3, 6 and 7 binding to the active site of Pseudomonas aeruginosa quorum sensing LasR system with better affinity compared to reference compounds 4-NPO. Finally, computation calculations suggest that compounds are a good template for further drug development.

Benzo[d]thiazole-2-thiol bearing 2-oxo-2-substituted-phenylethan-1-yl as potent selective lasB quorum sensing inhibitors and anti-biofilm formation of Pseudomonas aeruginosa.     

Hot exciton transition for organic light-emitting diodes: tailoring excited-state properties and electroluminescence performances of donor–spacer–acceptor molecules

The photophysical, electrochemical and electroluminescent properties of newly synthesized blue emitters with donor–π–acceptor geometry, namely, 4′-(1-(naphthalen-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl)-N,N-diphenyl-(2-[1,1′-biphenyl]vinyl)-4-amine (NSPI-TPA), 4′-(1-(2-methylnaphthalen-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl)-N,N-diphenyl-(2-[1,1′-biphenyl]vinyl)-4-amine (MNSPI-TPA), 4-(2-(4′-(diphenylamino)-(2-[1,1′-biphenyl]vinyl)-4-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)-1-naphthalene-1-carbonitrile (SPNCN-TPA) and 4-(2-(4-(9H-carbazol-9-yl)styryl)-1H-phenanthro[9,10-d]imidazol-1-yl)naphthalene-1-carbonitrile (SPNCN-Cz) were analyzed. The conjugation length in the emitters is not conducive to pure emission and hence, a molecular twisting strategy was adopted in NSPI-TPA, MNSPI-TPA, SPNCN-TPA and SPNCN-Cz to enhance pure emission. The emissive state (HLCT) of twisted D–π–A molecules containing both LE and CT (HLCT) states was tuned for high PL (η_PL) (LE) and high exciton utilization (η_s) (CT) efficiencies by replacing triphenylamine (strong donor) with carbazole (weak donor). Among strong donor compounds, namely, NSPI-TPA, MNSPI-TPA and SPNCN-TPA, the SPNCN-TPA-based device exhibited blue emission (451 nm) with CIE coordinates (0.15, 0.08), maximum current efficiency (η_c) of 2.32 cd A⁻¹, power efficiency (η_p) of 2.01 lm W⁻¹ and external quantum efficiency (η_ex) of 3.02%. The device with SPNCN-Cz emitter exhibited higher electroluminescence efficiencies than the SPNCN-TPA-based device, with pure blue emission (443 nm, CIE: 0.15,0.07), η_ex of 3.15%, η_c of 2.56 cd A⁻¹ and η_p of 2.45 lm W⁻¹.

SPNCN-Cz device exhibits η_ex (3.15%), η_c (2.56 cd A⁻¹), η_p (2.45 lm W⁻¹) with CIE (0.15, 0.07).     

Efficient donor–acceptor host materials for green organic light-emitting devices: non-doped blue-emissive materials with dual charge transport properties

Comparative optical, electroluminescence and theoretical studies were performed for (E)-4′-(1-(4-(2-(1-(4-morpholinophenyl)-1H-phenanthro[9,10-d]imidazol-2-yl)vinyl)phenyl)-1H-phenanthro[9,10-d]imidazol-2-yl)-N,N-diphenyl-[1,1′-biphenyl]-4-amine (SMPI-TPA) and (E)-4-(4-(2-(4-(2-(4-(9H-carbazol-9-yl)phenyl)-1H-phenanthro[9,10-d]imidazol-1-yl)styryl)-1H-phenanthro[9,10-d]imidazol-1-yl)phenyl)morpholine (SMPI-Cz). These compounds show excellent thermal properties, dual charge transport properties and form thin films under thermal evaporation. Blue OLEDs (CIE: 0.16, 0.08) based on SMPI-TPA show efficient device performance (η_ex 6.1%; η_c 5.3 cd A⁻¹; η_p 5.2 lm W⁻¹) at low turn-on voltages. Both SMPI-TPA and SMPI-Cz were utilised as hosts for green OLEDs. The devices with SMPI-Cz (30 nm):5 wt% Ir(ppy)₃ exhibit maximum luminance of 20 725 cd m⁻², and η_c and η_p values of 61.4 cd A⁻¹ and 63.8 lm W⁻¹, respectively. In comparison, devices with SMPI-TPA (30 nm):5 wt% Ir(ppy)₃ exhibit high η_c and η_p values of 65.2 cd A⁻¹ and 67.1 lm W⁻¹, respectively. Maximum η_ex values of 19.6% and 23.4% were obtained from SMPI-TPA:Ir(ppy)₃ and SMPI-Cz:Ir(ppy)₃, respectively. These device performances indicate that the phenanthroimidazole unit is a tunable building unit for efficient carrier injection and it may also be employed as a host for green OLEDs.

SMPI-Cz:Ir(ppy)₃-based devices exhibit a luminance of 20 725 cd m⁻², η_c of 61.4 cd A⁻¹ and η_p of 63.8 lm W⁻¹.     

In vitro and in silico determination of glutaminyl cyclase inhibitors

Alzheimer''s disease (AD) is the most common form of neurodegenerative disease currently. It is widely accepted that AD is characterized by the self-assembly of amyloid beta (Aβ) peptides. The human glutaminyl cyclase (hQC) enzyme is characterized by association with Aβ peptide generation. The development of hQC inhibitors could prevent the self-aggregation of Aβ peptides, resulting in impeding AD. Utilizing structural knowledge of the hQC substrates and known hQC inhibitors, new heterocyclic and peptidomimetic derivatives were synthesized and were able to inhibit the hQC enzyme. The inhibiting abilities of these compounds were evaluated using a fluorometric assay. The binding mechanism at the atomic level was estimated using molecular docking, free energy perturbation, and quantum chemical calculation methods. The predicted log(BBB) and human intestinal absorption values indicated that these compounds are able to permeate the blood–brain barrier and be well-absorbed through the gastrointestinal tract. Overall, 5,6-dimethoxy-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1H-benzo[d]imidazol-2-amine (1_2) was indicated as a potential drug for AD treatment.

Rational design of new hQC inhibitors.     

Identification of Five Structurally Unrelated Quorum-Sensing Inhibitors of Pseudomonas aeruginosa from a Natural-Derivative Database

Bacteria communicate by means of small signal molecules in a process termed quorum sensing (QS). QS enables bacteria to organize their activities at the population level, including the coordinated secretion of virulence factors. Certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), have been shown to effectively block QS and subsequently attenuate the virulence of Pseudomonas aeruginosa, as well as increasing its susceptibility to both antibiotics and the immune system. In this study, a structure-based virtual screening (SB-VS) approach was used for the discovery of novel QSI candidates. Three-dimensional structures of 3,040 natural compounds and their derivatives were obtained, after which molecular docking was performed using the QS receptor LasR as a target. Based on docking scores and molecular masses, 22 compounds were purchased to determine their efficacies as quorum-sensing inhibitors. Using a live reporter assay for quorum sensing, 5 compounds were found to be able to inhibit QS-regulated gene expression in P. aeruginosa in a dose-dependent manner. The most promising compound, G1, was evaluated by isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis, and it was found to significantly affect the abundance of 46 proteins (19 were upregulated; 27 were downregulated) in P. aeruginosa PAO1. It specifically reduced the expression of several quorum-sensing-regulated virulence factors, such as protease IV, chitinase, and pyoverdine synthetases. G1 was also able to reduce extracellular DNA release and inhibited the secretion of the virulence factor, elastase, whose expression is regulated by LasR. These results demonstrate the utility of SB-VS for the discovery of target-specific QSIs.     

Tailoring the molecular design of twisted dihydrobenzodioxin phenanthroimidazole derivatives for non-doped blue organic light-emitting devices

Three fused polycyclic aryl fragments, namely, naphthyl, methoxynaphthyl, and pyrenyl have been used to construct blue-emissive phenanthroimidazole-functionalized target molecules, i.e., 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(naphthalen-1-yl)-1H-phenanthro[9,10-d]imidazole (1), 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(1-methoxynaphthalen-4-yl)-1H-phenanthro[9,10-d]imidazole (2), and 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(pyren-10-yl)-1H-phenanthro[9,10-d]imidazole (3). The up-conversion of triplets to singlets via a triplet–triplet annihilation (TTA) process is dominant in these compounds due to 2E_T1 > E_S1. The pyrenyl dihydrobenzodioxin phenanthroimidazole (3)-based nondoped OLED exhibits blue emission (450 nm) with CIE (0.15, 0.14), a luminance of 53 890 cd m⁻², power efficiency of 5.86 lm W⁻¹, external quantum efficiency of 5.30%, and current efficiency of 6.90 cd A⁻¹. The efficient device performance of pyrenyl dihydrobenzodioxin phenanthroimidazole is due to the TTA contribution to the electroluminescent process.

Efficient blue emitters, 1-(2,3-dihydrobenzodioxinyl)-2-naphthylphenanthroimidazole, 1-(2,3-dihydrobenzodioxinyl)-2-methoxynaphthylphenanthroimidazole and 1-(2,3-dihydrobenzodioxinyl)-2-pyrenylphenanthroimidazole have been reported.     

Efficient fluorescent OLEDS based on assistant acceptor modulated HLCT emissive state for enhancing singlet exciton utilization

Phenylamine phenanthroimidazole based bipolar compounds with donor–acceptor (D–A) architecture namely, 4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6,9-di(pyren-4-yl)-1H-phenanthro[9,10-d]imidazol-2-yl)-N,N-diphenylaniline (DDPPPA) and 4′-(1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6,9-di(pyren-4-yl)-1H-phenanthro[9,10-d]imidazol-2-yl)-N,N-diphenyl-[1,1′-biphenyl]-4-amine (DDPBA) have been synthesized with highly fluorescent pyrene moieties at C6- and C9-positions. The C6 and C9 modification enhanced the thermal, photochemical and electroluminescent properties. Both molecules were employed as blue emitters in non doped organic light emitting devices (OLEDs) and show high performances due to hybridized local and charge-transfer properties. An OLED with DDPPPA/DDPBA emissive layer shows deep-blue emission with maximum external quantum efficiency (η_ex), current efficiency (η_c) and power efficiency (η_p) of 5.7/6.0%, 10.5/12.0 cd A⁻¹ and 8.3/9.2 lm W⁻¹, respectively. Both devices show high singlet exciton utilizing efficiency (η_s) of DDPPPA-31.33% and DDPBA-35.29%. The doped device m-MTDATA:DDPPPA/m-MTDATA:DDPBA shows maximum efficiencies of η_c −7.4/8.23 cd A⁻¹; η_p −5.8/6.13 lm W⁻¹; η_ex −4.72/5.63% (5 wt%):η_c −8.36/9.15 cd A⁻¹; η_p −6.32/6.65 lm W⁻¹; η_ex −4.86/5.45% (10 wt%):η_c −9.58/10.02 cd A⁻¹; η_p −7.8/8.25 lm W⁻¹; η_ex −5.96/6.25% (20 wt%). The doped device based on TAPC host TAPC:DDPPPA/TAPC:DDPBA exhibits maximum efficiencies of η_c −9.60/10.03 cd A⁻¹; η_p −7.81/8.26 lm W⁻¹; η_ex −5.96/6.25% (20 wt%).

OLED with C6/C9 substituted phenanthroimidazoles (DDPPPA/DDPBA) show blue emission with maximum external quantum efficiency (η_ex), current efficiency (η_c) and power efficiency (η_p) of 5.7/6.0%, 10.5/12.0 cd A⁻¹ and 8.3/9.2 lm W⁻¹, respectively.     

Coordination complexes constructed from pyrazole–acetamide and pyrazole–quinoxaline: effect of hydrogen bonding on the self-assembly process and antibacterial activity

Two mononuclear coordination complexes of N-(2-aminophenyl)-2-(5-methyl-1H-pyrazol-3-yl)acetamide (L₁), namely [Cd(L₁)₂Cl₂] (C₁) and [Cu(L₁)₂(C₂H₅OH)₂](NO₃)₂ (C₂) and one mononuclear complex [Fe(L₂)₂(H₂O)₂](NO₃)₂·2H₂O (C₃), obtained after in situ oxidation of L₁, have been synthesized and characterized spectroscopically. As revealed by single-crystal X-ray diffraction, each coordination sphere made of two heterocycles is completed either by two chloride anions (in C₁), two ethanol molecules (in C₂) or two water molecules (in C₃). The crystal packing analysis of C₁, C₂ and C₃, revealed 1D and 2D supramolecular architectures, respectively, via various hydrogen bonding interactions, which are discussed in detail. Furthermore, evaluation in vitro of the ligands and their metal complexes for their antibacterial activity against Escherichia coli (ATCC 4157), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC 25923) and Streptococcus fasciens (ATCC 29212) strains of bacteria, revealed outstanding results compared to chloramphenicol, a well-known antibiotic, with a normalized minimum inhibitory concentration as low as 5 μg mL⁻¹.

Two mononuclear coordination complexes of N-(2-aminophenyl)-2-(5-methyl-1H-pyrazol-3-yl)acetamide (L₁) and one mononuclear complex, obtained after in situ oxidation of L₁, have been synthesized and characterized spectroscopically.     

Synthesis and biological evaluation of the new ring system benzo[f]pyrimido[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepine and its cycloalkane and cycloalkene condensed analogues

Derivatives of the new ring system benzo[f]pyrimido[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepinone and its cycloalkane and cycloalkene condensed analogues have been conveniently synthesized through a three-step reaction sequence. An atom-economical, one-pot, three-step cascade process engaging five reactive centers (amide, amine, carbonyl, azide, and alkyne) has been performed for the synthesis of alicyclic derivatives of quinazolinotriazolobenzodiazepine using cyclohexane, cyclohexene, and norbornene β-amino amides. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy and X-ray crystallography. The reaction was also performed using enantiomeric starting materials leading to enantiomeric quinazolinotriazolobenzodiazepine with an ee of 95%. The synthesis of 9H-benzo[f]pyrimido[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepinone, a new heterocyclic system, was achieved in a good yield using a retro Diels–Alder (RDA) procedure. Some compounds were tested for antiproliferative activities against five human cancer cell lines of gynecological.

Derivatives of the new ring system benzo[f]pyrimido[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepinone and its cycloalkane and cycloalkene condensed analogues have been conveniently synthesized through a three-step reaction sequence.     

Inhibition of biofilm formation and quorum sensing mediated phenotypes by berberine in Pseudomonas aeruginosa and Salmonella typhimurium

Quorum sensing is involved in biofilm formation and modulates virulence factor production in pathogenic bacteria. Quorum sensing inhibitors can be used as novel intervention strategies for attenuating bacterial pathogenicity. Berberine is an isoquinoline alkaloid with pharmacological properties. The present study investigated the sub-inhibitory concentrations of berberine for inhibiting biofilm formation and quorum sensing regulated phenotypes in the bacterial pathogens Pseudomonas aeruginosa PA01 and Salmonella enterica serovar Typhimurium. Berberine inhibited quorum sensing regulated violacein production in C. violaceum. It reduced the pigment production in the wild type strain at 1.6 mg mL⁻¹ by 62.67%. In the opportunistic pathogen, P. aeruginosa PA01, at sub-MIC, it showed significant antibiofilm activity in by reducing biomass by 71.70% (p < 0.05). It prevented biofilm formation and inactivated biofilm maturation in bacterial pathogens at the concentration ranging from 0.019 to 1.25 mg mL⁻¹. In silico studies showed that berberine interacted with the quorum sensing signal receptors, LasR and RhlR. Furthermore, its anti-infective properties in S. Typhimurium were studied. At sub-inhibitory concentrations of 0.019 mg mL⁻¹, it reduced biofilm formation in S. Typhimurium by 31.20%. It significantly prevented invasion and adhesion of Salmonella invasion in the colonic cell, HT 29 by 55.37% and 54.68%, respectively. It was capable of reducing in vivo virulence in Caenorhabditis elegans infected with Salmonella at 0.038 mg mL⁻¹ by 65.38%. Our results suggest that berberine, previously recognised for its antimicrobial activity, could find potential application as an anti-biofilm and anti-infective agent based on its quorum sensing inhibitory activity.

Quorum sensing regulates violacein pigment production in C. violaceum.     

A “weak acid and weak base” type fluorescent probe for sensing pH: mechanism and application in living cells

A simple pH fluorescent probe, N-(6-morpholino-1, 3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl) isonicotinamide (NDI), based on naphthalimide as the fluorophore and isonicotinic acid hydrazide as the reaction site was synthesized and characterized. It is useful for monitoring acidic and alkaline pH. The results of pH titration indicated that NDI exhibits obvious emission enhancement with a pK_a of 4.50 and linear response to small pH fluctuations within the acidic range of 3.00–6.50. Interestingly, NDI also displayed strong pH-dependent characteristics with pK_a 9.34 and linearly responded to an alkaline range of 8.30–10.50. The sensing response mechanism was confirmed by ¹H NMR and ESI-MS spectroscopy. The mechanism of the optical responses of NDI toward pH was also determined by density functional theory (DFT) calculations. In addition, NDI displayed a highly selective and sensitive response to hydrogen ions and hydroxyl ions. The probe was successfully applied to image acidic and alkaline pH value fluctuations in HeLa cells and has lysosomal targeting ability.

When the probe was in the protonation process, the fluorescence intensity gradually decreased, whereas when the probe was in the deprotonation process, the fluorescence intensity gradually increased.     

Novel indole based hybrid oxadiazole scaffolds with N-(substituted-phenyl)butanamides: synthesis,lineweaver–burk plot evaluation and binding analysis of potent urease inhibitors

In the study presented herein, 4-(1H-indol-3-yl)butanoic acid (1) was sequentially transformed in the first phase into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3) and 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4) as a nucleophile. In the second phase, various electrophiles were synthesized by reacting substituted-anilines, 5a–j, with 4-chlorobutanoyl chloride (6) to afford 4-chloro-N-(substituted-phenyl)butanamides (7a–j). In the final phase, nucleophilic substitution reaction of 4 was carried out with different electrophiles, 7a–j, to achieve novel indole based oxadiazole scaffolds with N-(substituted-phenyl)butamides (8a–j). The structural confirmation of all the as-synthesized compounds was performed by spectral and elemental analysis. These molecules were screened for their in vitro inhibitory potential against urease enzyme and were found to be potent inhibitors. The results of enzyme inhibitory kinetics showed that compound 8c inhibited the enzyme competitively with a K_i value 0.003 μM. The results of the in silico study of these scaffolds were in full agreement with the experimental data and the ligands showed good binding energy values. The hemolytic study revealed their mild cytotoxicity towards cell membranes and hence, these molecules can be regarded as valuable therapeutic agents in drug designing programs.

In the study presented herein, 4-(1H-indol-3-yl)butanoic acid (1) was sequentially transformed in the first phase into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3) and 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4) as a nucleophile.     

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting materials viz. succinic anhydride, aminoguanidine hydrochloride, and a variety of amines. The choice of the pathway and sequence of the introduction of reagents to the reaction depended on the amine nucleophilicity. The first pathway started with the preparation of N-guanidinosuccinimide, which then reacted with amines under microwave irradiation to afford 5. The desired products were successfully obtained in the reaction with aliphatic amines (primary and secondary) via a nucleophilic opening of the succinimide ring and the subsequent recyclization of the 1,2,4-triazole ring. This approach however failed when less nucleophilic aromatic amines were used. Therefore, an alternative pathway, with the initial preparation of N-arylsuccinimides and their subsequent reaction with aminoguanidine hydrochloride under microwave irradiation, was applied. The annular prototropic tautomerism in the prepared 1,2,4-triazoles 5 was studied using NMR spectroscopy and X-ray crystallography.

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides were proposed and successfully realized in the synthesis of 20 representative examples.     

Persulfate-activated charcoal mixture: an efficient oxidant for the synthesis of sulfonated benzo[d][1,3]oxazines from N-(2-vinylphenyl)amides and thiols in aqueous solution

A series of 2,4-aryl-4-((arylsulfonyl)methyl)-4H-benzo[d][1,3]oxazines in good to excellent yields have directly been obtained from N-(2-vinylphenyl)amides and thiols by employing a mixture of K₂S₂O₈-activated charcoal in aqueous acetonitrile solution at 50 °C. A plausible mechanism for the reaction is reported. It reveals that the reaction follows a radical pathway and the persulfate has been the oxygen source for formation of the sulfone group in the products. It is worth mentioning that this protocol utilizes an easily accessible K₂S₂O₈-activated charcoal mixture and thiols, respectively, as an oxidant and sulfonylating precursors for the first time.

A simple method for the synthesis of 2,4-aryl-4-((arylsulfonyl)methyl)-4H-benzo[d][1,3]oxazines using an easily accessible K₂S₂O₈-activated charcoal mixture and thiols, respectively, as an oxidant and sulfonylating precursors has been described.     

Induction of Plasmid-Carried qnrS1 in Escherichia coli by Naturally Occurring Quinolones and Quorum-Sensing Signal Molecules

Naturally occurring quinolone and quinolone-like compounds, such as quinine, 2-hydroxyquinoline, 4-hydroxyquinoline, and 2-heptyl-3-hydroxy-4(1H)-quinolone, increased expression of qnrS1 in Escherichia coli 2.3- to 11.2-fold, similar to the synthetic quinolone ciprofloxacin. In contrast, chromosomal qnrVS1 of Vibrio splendidus was not induced by these compounds. Molecules associated with quorum sensing, such as N-3-hydroxybutyryl-homoserine lactone (HSL), N-hexanoyl-HSL, and N-3-(oxododecanoyl)-HSL, did not show an induction effect on either qnrS1 or qnrVS1 at the tested concentrations.