Derivatives 4e Research Articles

Synthesis and biological evaluation of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses, a new class of α-glucosidase inhibitors

A series of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a–e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.

Synthesis and bioactive evaluation of a novel series of coumarinazoles

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d–e showed better anti-Candida utilis activity than mono-azole derivatives 4a and 4d–e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-Candida albicans and anti-Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti-Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.

Synthesis and antiproliferative activity of conjugates of adenosine with muramyl dipeptide and nor-muramyl dipeptide derivatives

We synthesized a series of MDP(D,D) and nor-MDP(D,D) derivatives conjugated with adenosine through a spacer as potential immunosuppressants. New conjugates 8a–k were evaluated on two leukemia cell lines (Jurkat and L1210) and PBMC from healthy donors. The conjugates 8a–k and MDP(D,D)/nor-MDP(D,D) derivatives 7e, f, i, j were active against L1210 cell line. Unconjugated nor-MDP(D,D) had better antiproliferative properties, but the conjugates 8b, f, g had the highest values of selectivity index. Both cell lines as well as PBMC were resistant to analogs 11a, b with the 6-aminohexanoic linker.

Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3‐a] tetrahydrobenzo (b) thieno [3, 2‐e] pyrimidine‐5(4H)‐ones

Triazolo[4,3‐a]tetrahydrobenzo(b)thieno[3,2‐e]pyrimidine‐5(4H)‐ones (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m were synthesized and characterized by spectral analysis. All 13 derivatives were evaluated for central nervous system (CNS) depressant and skeletal muscle relaxant activities in Swiss albino mice. All the activities were compared with diazepam as a standard drug at a dose of 5 mg/kg. The most active derivatives 5d, 5e, 5k, and 5l in CNS depressant and skeletal muscle relaxant activities were selected for anticonvulsant activity. The active derivatives were found to protect 100% mice at the dose of 6–11 mg/kg, where as standard diazepam protect the animal at a dose of 2.5 mg/kg.

Novel curcumin analogue IHCH exhibits potent anti‑proliferative effects by inducing autophagy in A549 lung cancer cells.

Curcumin is a natural polyphenolic compound that exhibits strong antioxidant and anticancer activities; however, low bioavailability has restricted its application in chemotherapeutic trials. The present study aimed to investigate the anticancer effect of the novel curcumin derivative 2E,6E‑2‑(1H‑indol‑3‑yl) methylene)‑6‑(4‑hydroxy‑3‑methoxy benzylidene)‑cyclohexanone (IHCH) on A549 lung cancer cells. Cells were treated with IHCH at different concentrations (1‑40µM) for different time periods (1‑36h). Microscopic analysis revealed that IHCH inhibited A549 cell growth and induced the formation of characteristic autophagolysosomes in a dose‑ and time‑dependent manner. Furthermore, the inhibitory rate of IHCH (40µM) on A549 cell viability was 77.34% after 36h of treatment. Acridine orange staining revealed an increase in autophagic vacuoles in the IHCH‑treated A549 cells. Monodansylcadaverine staining was used to analyze autophagy rate. Immunocytochemistry revealed an increase in light chain (LC)3 protein expression in the IHCH‑treated cells and western blot analysis detected the conversion of LC3‑I to LC3‑II, as well as the recruitment of LC3 to autophagosomes in the cytoplasmatic compartment, suggesting the occurrence of autophagy. These findings show that IHCH induced autophagy in A549cells, which is a novel cell death mechanism induced by curcumin derivatives.

Experimental and theoretical (FT-IR, FT-Raman, UV–vis, NMR) spectroscopic analysis and first order hyperpolarizability studies of non-linear optical material: (2E)-3-[4-(methylsulfanyl) phenyl]-1-(4-nitrophenyl) prop-2-en-1-one using density functional theory

A combined experimental and theoretical investigation on FT-IR, FT-Raman, NMR, UV–vis spectra of a chalcone derivative (2E)-3-[4-(methylsulfanyl) phenyl]-1-(4-nitrophenyl) prop-2-en-1-one (4N4MSP) has been reported. 4N4MSP has two planar rings connected through conjugated double bond and it provides a necessary configuration to show non-linear optical (NLO) response. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on density functional theory (DFT) with B3LYP functional and 6-311++G(d,p) basis set combination. The analysis of the fundamental modes was made with the help of potential energy distribution (PED). Molecular electrostatic potential (MEP) surface was plotted over the geometry primarily for predicting sites and relative reactivities towards electrophilic and nucleophilic attack. The delocalization of electron density of various constituents of the molecule has been discussed with the aid of NBO analysis. The electronic properties, such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies, were calculated by time-dependent density functional theory (TD-DFT) and the results complement the experimental findings. The recorded and calculated 1H chemical shifts in gas phase and MeOD solution are gathered for reliable calculations of magnetic properties. Thermodynamic properties like heat capacity (C°p,m), entropy (S°m), enthalpy (H°m) have been calculated for the molecule at the different temperatures. Based on the finite-field approach, the non-linear optical (NLO) parameters such as dipole moment, mean polarizability, anisotropy of polarizability and first order hyperpolarizability of 4N4MSP molecule are calculated. The predicted first hyperpolarizability shows that the molecule has a reasonably good nonlinear optical (NLO) behavior.

Norbornanoid Chiral Ketones by Desymmetrization of Dibromoalkenes

AbstractNew optically active polycyclic ketones 6a–6d, amenable to a large variety of synthetic applications, have been prepared from readily available 2,3‐dibromonorbornene and analogs (Scheme 2) via desymmetrization with (−)‐ephedrine, followed by hydrolysis under mild acidic conditions. At variance with substrates 4a–4d, the sterically hindered norbornene derivative 4e reacts with the solvent N‐methylpyrrolidin‐2‐one (NMP) leading to the formation of the unusual cyclopropanoid products 8a and 8b.

Design, synthesis and evaluation of novel diaryl pyrrolopyrimidine and pyrrolothiazine derivatives as inhibitors of tumor necrosis factor stimulated gene-14 (TSG-14) production

A novel series of pyrrolothiazines 2–4 and pyrrolopyrimidines 5–7 have been synthesized. The structures of these compounds were established by spectroscopic and element microanalytical data. The newly synthesized compounds were evaluated as inhibitors of TSG-14. The most effective results were obtained by the S-sec-butyl derivatives 6e (80%) and the N-ethyl derivatives 4e (70%).

4‐Hydroxy‐α‐Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant Escherichia coli

The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy-α-tetralone (1) isolated from Ammannia spp. along with its semi-synthetic derivatives (1a-1e) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT-PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product.

Emergence of pyrido quinoxalines as new family of antimalarial agents

A series of novel N-alkyl dihydro pyrido quinoxaline derivatives were synthesized using Gould–Jacobs reaction and evaluated their antimalarial activity in vitro against chloroquine sensitive (3D7) and drug resistant (Dd2) strains of Plasmodium falciparum. Among the compounds tested, 10 compounds were more potent than their structural standard analog ciprofloxacin, including 2 derivatives 5e and 5h, which showed 3.3–7.4 times more potency than ciprofloxacin against both the parasite strains. The results are encouraging and a lead molecule may emerge which is useful alone or in combination therapy.

Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: Design, synthesis and evaluation as potential anti-inflammatory agents

Novel series of celecoxib analogs endowed with benzofuran moiety 3a–e and 9a–d were synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro. The most potent and selective COX-2 inhibitors – compounds 3c, 3d, 3e, 9c and 9d – were assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivatives 3c and 3e exhibited the highest anti-inflammatory activity, that is equipotent to celecoxib. Furthermore, the tested compounds proved to have better gastric safety profile compared to celecoxib. In particular, compound 3e demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug. Finally, molecular docking simulation of the new compounds in COX-2 active site and drug likeness studies showed good agreement with the obtained pharmaco-biological results.

The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether

Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5mg/kg of dimer secondary alcohol 6a or 6b plus 15mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25–27days) of malaria-infected mice.

Synthesis, biological evaluation, and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents

A series of pyrazolyl-acylhydrazone derivatives (1e–20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC50 = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Synthesis and chemical–optical characterization of novel two-photon fluorescent borinates derived from Schiff bases

Herein is reported the synthesis and characterization of eight borinates (2a–h) prepared from the reaction of the corresponding bidentate imine ligands (1a–h) and diphenylborinic acid. All compounds were characterized by MS, IR and NMR spectroscopies whereas the molecular structures of derivatives 2c and 2e were also studied by X-ray diffraction analysis that corroborated the presence of a tetra-coordinated boron atom. In addition, the linear and nonlinear optical (NLO) characterization of these molecules having D–π–CN+–π–D and D–π–CN+–π–A electronic systems was performed, i.e., the third-order nonlinear optical responses were measured by using the two-photon excited fluorescence and the third-harmonic generation (χ3 determination) techniques. The borinates showed two-photon absorption (2PA) effect in solution under femtosecond excitation: 2g and 2h having D–π–CN+–π–A architecture showed the largest 2PA cross-sections (σ2PA) values at 760 nm: 124 and 174 GM (1 GM = 10−50 cm4 s), respectively, while the values for 2e and 2f that possess D–π–CN+–π–D structure were 12 and 37 GM. The χ3 values, with nanosecond excitation, were of the order of 10−12 esu at 1200 nm.

In-silico docking based design and synthesis of [1H,3H] imidazo[4,5-b] pyridines as lumazine synthase inhibitors for their effective antimicrobial activity.

Purpose:The imidazopyridine moiety is important pharmacophore that has proven to be useful for a number of biologically relevant targets, also reported to display antibacterial, antifungal, antiviral properties. Riboflavin biosynthesis involving catalytic step of Lumazine synthase is absent in animals and human, but present in microorganism, one of marked advantage of this study. Still, this path is not exploited as antiinfective target. Here, we proposed different interactions between [1H,3H] imidazo[4,5-b] pyridine test ligands and target protein Lumazine synthase (protein Data Bank 2C92), one-step synthesis of title compounds and further evaluation of them for in vitro antimicrobial activity.Materials and Methods:Active pocket of the target protein involved in the interaction with the test ligands molecules was found using Biopredicta tools in VLifeMDS 4.3 Suite. In-silico docking suggests H-bonding, hydrophobic interaction, charge interaction, aromatic interaction, and Vanderwaal forces responsible for stabilizing enzyme-inhibitor complex. Disc diffusion assay method was used for in vitro antimicrobial screening.Results and Discussion:Investigation of possible interaction between test ligands and target lumazine synthase of Mycobacterium tuberculosis suggested 1i and 2f as best fit candidates showing hydrogen bonding, hydrophobic, aromatic and Vanderwaal's forces. Among all derivatives 1g, 1j, 1k, 1l, 2a, 2c, 2d, 2e, 2h, and 2j exhibited potent activities against bacteria and fungi compared to the standard Ciprofloxacin and Fluconazole, respectively. The superiority of 1H imidazo [4,5-b] pyridine compounds having R’ = Cl >No2 > NH2 at the phenyl/aliphatic moiety resident on the imidazopyridine, whereas leading 3H imidazo[4,5-b] pyridine compounds containing R/Ar = Cl > No2 > NH2> OCH3 substituents on the 2nd position of imidazole.

Synthesis andin vitroEvaluation of New Benzenesulfonamides as Antileishmanial Agents

This paper describes the synthesis and the antileishmanial activity of new pyrazolyl benzenesulfonamide derivatives. These were elucidated by spectrometric methods. Some compounds showed a significant in vitro activity against Leishmania amazonensis, highlighting the derivative 1e. These pyrazolyl benzenesulfonamide derivatives did not show any toxicity in murine macrophage.

Synthesis and Antimicrobial Activity of Some New N‐substituted‐5‐arylidene‐thiazolidine‐2,4‐diones

A total of 17 new N‐substituted derivatives (2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k and 3b, 3c, 3d, 3e, 3f, 3g, 3h) of 5‐((2‐phenylthiazol‐4‐yl)methylene) thiazolidine‐2,4‐dione (2a) and 5‐(2,6‐dichloro‐ benzylidene)thiazolidine‐2,4‐dione (3a) were synthesized. The structural elucidation of the newly synthesized compounds was based on elemental analysis and spectroscopic data (MS, 1H NMR, 13C NMR), and their antimicrobial activities were assessed in vitro against several strains of Gram‐positive and Gram‐negative bacteria and one fungal strain (Candida albicans) as growth inhibition diameter. Some of them showed modest to good antibacterial activity against Gram‐negative Escherichia coli and Salmonella typhimurium and Gram‐positive Staphylococcus aureus, Bacillus cereus, and Enterococcus fecalis bacterial strains, whereas almost all the compounds were inactive against Listeria monocytogenes. All of the synthesized compounds showed moderate to very good activity against C. albicans.

Synthesis, characterization, and computational studies on phthalic anhydride-based benzylidene-hydrazide derivatives as novel, potential anti-inflammatory agents

A series of phthalic anhydride-based substituted benzylidene-hydrazide derivatives (3a–i) was synthesized. The synthesized derivatives were authenticated by TLC, UV–visible, FTIR, NMR, and mass spectroscopic techniques and further screened for in vivo anti-inflammatory and analgesic activities by carrageenan-induced rat paw oedema and tail immersion methods, respectively, using diclofenac sodium as standard drug. The derivatives 3d, 3e, and 3h were found to be most active anti-inflammatory and analgesic agents among all the synthesized derivatives. The physico-chemical similarity of the derivatives with standard drugs was assessed by calculating various physicochemical properties using software programs. The percent similarity of synthesized derivatives was found to be good except 3i. The derivatives were subjected to QSAR by multilinear regression using Analyze it version 3.0 software and two statistically sound models were developed with R 2 (0.933–0.960), $$ R_{{adj}}^{2} $$ (0.595–0.762) and Q 2 (0.999) with good F (2.76–4.84) values. Molecular docking studies were performed by MVD software (version 2012.5.0.0). The derivative 3h has emerged out as most potent anti-inflammatory agent with highest dock score, i.e., −93.64.

Synthesis and Antimycobacterial Activity of Novel Thiadiazolylhydrazones of 1‐Substituted Indole‐3‐carboxaldehydes

A series of novel thiocarbohydrazones of substituted indoles and their corresponding thiadiazole derivatives were prepared, and their structures were confirmed by different analytical and spectroscopic methods. The derivatives were prepared by a sequential synthetic strategy including substitution at N-1 position of indole ring by various aliphatic and benzylic substituents, followed by condensation with thiocarbohydrazide, and finally cyclization by triethyl orthoformate. The derivatives were tested for their antimycobacterial activity against Mycobacterium bovis BCG, and the results revealed that among the synthesized compounds, thiadiazole derivatives 4e, 4f, 4n, 4p, 4q, and 4t exhibited the highest activity with IC₅₀ value of 3.91 μg/mL. The results indicate that the thiadiazole moiety plays a vital role in exerting antimycobacterial activity.

Synthesis, biological evaluation and docking studies of 4-aryloxymethyl coumarins derived from substructures and degradation products of vancomycin

Two series of 4-aryloxymethyl coumarins derived from the reaction of 4-bromomethyl coumarins with ethyl gallate and ethyl ester of N-Benzoyl tyrosine have been synthesized. Gallate ethers 3a–3g and tyrosine derivatives 4e–4j were most effective against Entercoccus faecalis. They were also found to be effective against Aspergillus niger and Candida albicans. Comparative docking studies with novobiocin have indicated better binding ability and higher ‘C’ score values than novobiocin.