7a 7d Research Articles

Biochemical and in silico inhibition of bovine and human carbonic anhydrase-II by 1H-1,2,3-triazole analogs.

A series of 1H-1,2,3-triazole analogs (7a-7d and 9a-9s) were synthesized via "click" chemistry and evaluated for in vitro carbonic anhydrase-II (bovine and human) inhibitory activity. The synthesis of intermediates, 7a and 7c, was achieved by using (S)-(-)ethyl lactate as a starting material. These compounds (7a and 7c) underwent Suzuki-Miyaura cross-coupling reaction with different arylboronic acids in 1,4-dioxane, reflux at 90-120°C for 8h using Pd(PPh3)4 as a catalyst (5mol%), and K2CO3 (3.0 equiv)/K2PO4 (3.0 equiv) as a base to produce target 1H-1,2,3-triazole molecules (9a-9s) for a good yield of 67-86%. All the synthesized compounds were characterized through NMR spectroscopic techniques. Furthermore, all those compounds have shown significant inhibitory potential for both sources of carbonic anhydrase-II (CA-II). In the case of bCA-II, compounds 9i, 7d, 9h, 9o, 9g, and 9e showed potent activity with IC50 values in the range of 11.1-17.8µM. Whereas for hCA-II, compounds 9i, 9c, 9o, and 9j showed great potential with IC50 values in the range of 10.9-18.5µM. The preliminary structure-activity relationship indicates that the presence of the 1H-1,2,3-triazole moiety in those synthesized 1H-1,2,3-triazole analogs (7a-7d and 9a-9s) significantly contributes to the overall activity. However, several substitutions on this scaffold affect the activity to several folds. The selectivity index showed that compounds 9c, 9k, and 9p are selective inhibitors of hCA-II. Kinetics studies showed that these compounds inhibited both enzymes (bCA-II and hCA-II) in a competitive manner. Molecular docking indicates that all the active compounds fit well in the active site of CA-II. This study has explored the role of 1H-1,2,3-triazole-containing compounds in the inhibition of CA-II to combat CA-II-related disorders.

Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer

New series of thiazolyl-pyrazoline derivatives (7a–7d, 10a–10d and 13a–13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC50 = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC50 = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC50 = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC50 = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.

Synthesis of novel luminescent cyclometallated platinum (IV) complexes with a quinoline Schiff bases ligand and their photophysical properties

The synthesis, characterization, electro and photophysical properties of eight cyclometallated platinum (IV) complexes 6a–6d and 7a–7d derived from quinoline Schiff base ligands are reported. Spectral studies revealed that nonparticipation of nitrogen atom and participation of carbon atom of the quinoline ring in the bond formation through [NN′C] mode of coordination for complex 6, whereas [N S O] mode of coordination with octahedral geometry for complex 7. The absorption and emission spectra studied in acetonitrile medium at room temperature showed that the ligand charge transitions within the quinoline Schiff base ligands with Metal Ligand Charge Transfer (MLCT) character. The broad band appeared in the range of 460–502 nm is attributed to the higher emission intensities of cyclometallated platinum (IV) compounds. The HOMO, LUMO and energy gap of the synthesized complexes was found to be − 2.60 eV, −4.75 eV and 2.15 eV through Density Functional Theory (DFT).

Synthesis of Enantiomerically Pure N-Boc-Protected 1,2,3-Triaminopropylphosphonates and 1,2-Diamino-3-Hydroxypropylphosphonates.

All possible isomers of 1,2,3-tri(N-tert-butoxycarbonylamino)propylphosphonate 6 were synthesized from the respective diethyl [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates 5 via opening the aziridine ring with trimethylsilyl azide (TMSN3) followed by hydrogenolysis in the presence of di-tert-butyl dicarbonate (Boc2O). [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1R,2R,1′S)-5a and (1S,2S,1′R)-5c were smoothly transformed into diethyl 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates (1R,2R,1′S)-9a and (1S,2S,1′R)-9c, respectively by the opening of the aziridine ring with acetic acid. Transformations of [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1S,2R,1′S)-5b and (1R,2S,1′R)-5d into diethyl 3-acetoxy-1-benzylamino-2-[(1-phenylethyl)amino]propylphosphonates (1S,2R,1′S)-9b and (1R,2S,1′R)-9d were accompanied by the formation of ethyl {1-(N-benzylacetamido)-3-hydroxy-2-[(1-phenylethyl)amino]propyl}phosphonate (1S,2R,1′S)-10b and (1R,2S,1′R)-10d and 3-(N-benzylacetamido)-4-[N-(1-phenylethyl)]amino-1,2-oxaphospholane (3S,4R,1′S)-11b and (3R,4S,1′R)-11d as side products. Diethyl (1R,2R)-, (1S,2S)-, (1S,2R)- and (1R,2S)-3-acetoxy-1,2-di(N-tert-butoxycarbonylamino)propylphosphonates 7a–7d were obtained from the respective 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates 9a–9d by hydrogenolysis in the presence of Boc2O.

New Chalcone Derivatives with Schiff Base-Thiophene: Synthesis, Biological Activity, and Molecular Docking Studies

New thiophene chalcones 3, 6 and thiophene Schiff base-chalcone derivatives 4a–4d, 7a–7d are synthesized. Structures of the compounds are confirmed by 1H and 13C NMR, and IR spectra. According to antimicrobial and antileishmanial tests, the compounds 4c–7c demonstrate efficient antileishmanial and antimicrobial activities. Molecular docking studies based on Maestro Molecular Modeling indicate 4c and 7c to be the most potent compounds that are characterized by the least docking score,–10.674 and–10.989 kcal/mol, respectively.

Synthesis and Antitumor Activity of Some New Fused Heterocyclic Compounds

Reaction of thiopyrimidine derivative 3 with hydrozonoyl chlorides 4a–4e gives new fused heterocyclic compounds 7a–7e containing triazole ring. The latter demonstrates a wide range of biological activities. Thiazolone pyridopyrimidines 8, 9a, 9b are prepared by the reaction of thiopyrimidines with chloroacetic acid and different aromatic aldehydes in the presence of acetic anhydride. Bis-arylidene 2 reacts with malononitrile or ethyl cyanoacetate with formation of carbonitrile derivatives 10, 11. Reaction of bisarylidene 2 with phenyl hydrazine and hydrazine hydrate leads to diazole derivatives 12, 13. Structures of the new compounds are elucidated from IR, 1H and 13C NMR, and mass spectra. All newly synthesized products are tested for antitumor activity on three human tumor cell lines, including prostatic adenocarcinoma (PC3), human colorectal carcinoma (HCT116), human liver hepatocellular carcinoma (HepG2) and breast carcinoma (MCF7). Compounds 2, 7a–7d demonstrate the considerable potency.

Synthesis of novel 2H-chromene-3-carboxylate isoxazole/isoxazoline derivatives via 1,3-dipolar cycloaddition reaction (NOAC)

Synthesis of novel (3-phenylisoxazol-5-yl)methyl-2H-chromene-3-carboxylates (7a–7d) and (3-phenyl-4,5-dihydroisoxazol-5-yl)methyl-2H-chromene-3-carboxylates (8a–8p) by 1,3-dipolar cycloaddition, and nitrile oxide and alkyne cycloaddition (NOAC) is presented. The products are characterised by IR, 1H and 13C NMR, and ESI-MS data.

Prediction of blood-brain barrier penetration of meta-/para-Alkoxyphenylcarbamic acid Esters bearing substituted N-Phenylpiperazine fragment

The present study deals with blood-brain barrier (BBB) passive penetration of the substances labelled as 7a–7d and chemically referred to as 1-[3-(Y-alkoxyphenylcarbamoyloxy)-2-hydroxypropyl]-4-(2-methylphenyl) piperazinium chlorides. Following their chemical structures, they could be classified as prospective ?-/?-adrenoceptor blockers. Such groups are known, among others, by their adverse reactions on central nervous system due to their transport across the BBB. The lipophilicity as the main parameter of the BBB permeability predictions is presented by the values of partition coefficient which was experimentally estimated using shake-flask method in two different partitions, i.e. in octan-1-ol/buffer and cyclohexane/buffer as well. The in silico models which were used are based on the correlation between the log BB and the ? log P readouts (the log P value estimated in octan-1-ol/buffer minus the one estimated in cyclohexane/buffer) whereby log BB is primary transfer marker for such compounds entering brain from blood. Besides the log BB outputs, some other molecular physicochemical descriptors have to be generated. According to the results obtained by using Young, Kaliszan, Kelder, Clarks, Pan, Abraham, Feher and van de Waterbeemd models, probably none of the currently investigated compounds will permeate across the BBB. DOI: http://dx.doi.org/10.3329/dujps.v13i1.21854 Dhaka Univ. J. Pharm. Sci. 13(1): 7-14, 2014 (June)

Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2, 5-dione derivatives as anticonvulsants

A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a–7d, 8a–8d, 9a–9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs.

New triphenylamine-based poly(amine-imide)s with carbazole-substituents for electrochromic applications

A new carbazole-derived triphenylamine-containing diimide-diacid monomer (5), 4,4′-bis(trimellitimido)-4″-N-carbazolytriphenylamine, is prepared by the condensation of 4,4′-diamino-4″-N-carbazolytriphenylamine (4) and two molar equivalents of trimellitic anhydride (TMA). A series of new poly(amide-imide)s (PAIs) 7a–7d with carbazole-substituted triphenylamine units are prepared by direct polymerization from the new diimide-diacid (5) and various aromatic diamines (6a–6d). The PAIs shows high glass transition temperature between 269 and 297°C, and high 5% weight loss temperature between 526 and 561°C under nitrogen environment. Cyclic voltammograms of the PAIs films, which are casted onto the indium–tin oxide (ITO)-coated glass substrate, exhibit two reversible oxidation redox couples at 1.05–1.08V and 1.38–1.46V under an anodic sweep. The PAI-7a film reveals excellent stability of electrochromic characteristics for the radical cations generated, changing color from original pale yellowish neutral form to the green and then to dark blue oxidized forms. Furthermore, the anodically coloring of PAI-7a shows high coloration efficiency (CE=205cm2/C), high contrast of optical transmittance change (ΔT=80% at 776nm) and long-term redox reversibility.

Novel synthetic acridine-based derivatives as topoisomerase I inhibitors

Abstract Novel DNA binding agents against topoisomerases are needed for effective treatment of cancers. A series of new acridine-based derivatives 7a–7d were synthesized and their antiproliferative activity against K562 and HepG-2 cell lines were evaluated. Compound 7c with pyridin-2-yl-methanamino group substituted at the C9 position of acridine showed good antitumor activity against both cell lines. The DNA-binding affinity of compound 7c was evaluated by UV–vis absorption spectra and fluorescence emission spectra. DNA topoisomerase I mediated relaxation of plasmid pBR322 DNA was also tested. Our results suggested that compound 7c with good antitumor activity and topoisomerase I inhibition activity can be developed as a prime candidate for further chemical optimization.

New 6-bromoimidazo[1,2-a]pyridine-2-carbohydrazide derivatives: synthesis and anticonvulsant studies

In the present work, we report the facile synthesis and anticonvulsant study of new imidazo[1,2-a]pyridines carrying biologically active hydrazone functionality (3a–3e) and suitably substituted 1,2,4-triazole moieties (4, 5a–5d, 6, and 7a–7d). The newly synthesized intermediates and final compounds were characterized by various spectral techniques such as FTIR, 1H NMR, 13C NMR, and mass spectral and elemental analysis studies. The in vivo anticonvulsant study of the target compounds were carried out following maximal electroshock seizure and subcutaneous pentylene tetrazole methods, while their toxicity study was performed following rotarod method by taking 20, 40, and 100 mg/kg dose levels. Most of the new compounds displayed remarkable anticonvulsant properties at these doses. Particularly, compounds 3b and 4 carrying hydrogen bond donor groups, viz. hydroxyl and amine moieties respectively, exhibited complete protection against seizure and their results are comparable to that of standard drug diazepam. Further, the motor impairment study revealed that all the compounds are nontoxic upto 100 mg/kg.

Synthesis, anticonvulsant activity and molecular properties prediction of dialkyl 1-(di(ethoxycarbonyl)methyl)-2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-dicarboxylates

The synthesis and anticonvulsant properties of new N-diethylmalonyl derivatives of nifedipine and other isosteric analogues (7a–7n) were described. Anticonvulsant screening was performed by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizures tests. Majority of the compounds were effective in scPTZ and MES screens. Compound 7k showed good activity displaying maximum protection, which may be due to the presence of styryl moiety at position 4 of 1,4-dihydropyridine nucleus and the methyl groups of diester functionality. Compounds 7a–7d, 7g, 7i and 7k obeyed the Lipinski's “rule of five” and have drug-likeness. Based on computational prediction of molecular and pharmacokinetic properties, it was found that the compounds have good oral absorption.

Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands

A series of 1,8-dipyrazolcarbazole (DPC) derivatives (6a–6d, 7a–7d) designed as G-quadruplex ligands have been synthesized and characterized. The FRET-melting and SPR results showed that the DPC derivatives could well recognize G-quadruplex with strong discrimination against the duplex DNA. In addition, the DPC derivatives showed much stronger stabilization activities and binding affinities for c-myc G-quadruplex rather than telomeric G-quadruplex. Therefore, their interactions with c-myc G-quadruplex were further explored by means of CD spectroscopy, PCR-stop assay, and molecular modeling. In cellular studies, all compounds showed strong cytotoxicity against cancer cells, while weak cytotoxicity towards normal cells. RT-PCR assay showed that compound 7b could down-regulate c-myc gene expression in Ramos cell line, while had no effect on c-myc expression in CA46 cell line with NHE III1 element removed, indicating its effective binding with G-quadruplex on c-myc oncogene in vivo.

Synthesis of {2,3-Dihydro-7-halopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-Dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one}: New Analogs of Deoxyvasicinone

A series of novel halogen-substituted deoxyvasicinone {2,3-dihydro-7-halopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one} derivatives was synthesized by condensation of halogenated anthranilic acids (2, 3, 4, 5) with 4-aminobutyric acid (6) in refluxing m-xylene over phosphorus pentoxide for 3 h to give the desired compounds (7a–7d).

ChemInform Abstract: Synthesis of New Nucleoside Analogues Comprising a Geminal Difluorocyclopropane Moiety as Potential Antiviral/Antitumor Agents.

Abstract Geminal difluorocyclopropane analogues of nucleosides 7a–7e were synthesized. Compounds 7a and 7c–7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a–7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.

Synthesis and evaluation of new N6-substituted adenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists

A number of N6-substituted adenosine-5′-N-methylcarboxamides were synthesised and their pharmacology, in terms of their receptor affinity, selectivity and cardioprotective effects, were explored. The first series of compounds, 4a–4f and 5a–5f, showed modest receptor affinity for the A3AR with Ki values in the low to mid μM range. However, the incorporation of a 4-(2-aminoethyl)-2,6-di-tert-butylphenol group in the N6-position (in compounds 4g and 5g) significantly improved the affinity with Ki values of 30 and 9nM, respectively. Improvements in affinity, as well as selectivity were seen when a functionalised linker was introduced. The N6-phenyl series, compounds 7a–7d, demonstrated low to mid nanomolar receptor affinities (Ki=2.3–45.0nM), with 7b displaying 109-fold selectivity for the A3AR (vs A1). The N6-benzyl series 9a–9c also proved to be potent and selective A3AR agonists and the longer chain length linker 13 was tolerated at the A3AR without abrogation of affinity or selectivity. Cardioprotection was demonstrated by a simulated ischaemia cell culture assay, whereby 7b, 7c, 9a, 9b and 9c all showed cardioprotective effects at 100nM comparable or better than the benchmark A3AR agonist IB-MECA, but which were indistinguishable by statistical analysis. For example, compound 9c reduced cell death by 68.0±3.6%.

Metal‐mediated gem‐Difluoroallylation of N‐Acylhydrazones: Highly Efficient Synthesis of α,α‐Difluorohomoallylic Amines

AbstractIndium‐mediated gem‐difluoroallylation of aldehyde‐derived N‐acylhydrazones 1a–1q and 4a–4g with 3‐bromo‐3,3‐difluoropropene 2 afforded α,α‐difluorohomoallylic hydrazides 3a–3q and 5a–5g in high yields, respectively. Functional groups such as nitro, phenolic hydroxyl, benzyloxy and even C=C bonds of α,β‐unsaturated aldehydes were compatible under this mild and operationally simple gem‐difluoroallylic reaction condition. By means of substitution of Zn powder for indium, gem‐difluoroallylation of ketone‐derived N‐acylhydrazones 6a–6d also provided the corresponding α,α‐difluorohomoallylic hydrazides 7a–7d in medium yields. The N–N bond cleavage of the hydrazide 3a proceeded smoothly to give the corresponding primary gem‐difluorohomoallylic amine 8, which could be converted to gem‐difluoro‐δ‐substituted α,β‐unsaturated lactam 11 via acryloylation followed by ring closing metathesis (RCM) reaction.

An Alternative Domain Near the Nucleotide-binding Site of Drosophila Muscle Myosin Affects ATPase Kinetics

In Drosophila melanogaster expression of muscle myosin heavy chain isoforms occurs by alternative splicing of transcripts from a single gene. The exon 7 domain is one of four variable regions in the catalytic head and is located near the nucleotide-binding site. To ascribe a functional role to this domain, we created two chimeric myosin isoforms (indirect flight isoform-exon 7a and embryonic-exon 7d) that differ from the native indirect flight muscle and embryonic body-wall muscle isoforms only in the exon 7 region. Germline transformation and subsequent expression of the chimeric myosins in the indirect flight muscle of myosin-null Drosophila allowed us to purify the myosin for in vitro studies and to assess in vivo structure and function of transgenic muscles. Intriguingly, in vitro experiments show the exon 7 domain modulates myosin ATPase activity but has no effect on actin filament velocity, a novel result compared to similar studies with other Drosophila variable exons. Transgenic flies expressing the indirect flight isoform-exon 7a have normal indirect flight muscle structure, and flight and jump ability. However, expression of the embryonic-exon 7d chimeric isoform yields flightless flies that show improvements in both the structural stability of the indirect flight muscle and in locomotor abilities as compared to flies expressing the embryonic isoform. Overall, our results suggest the exon 7 domain participates in the regulation of the attachment of myosin to actin in order to fine-tune the physiological properties of Drosophila myosin isoforms.

Thermal Isomerization of Isoborneols and Dehydroisoborneols to New Chiral Building Blocks in Terpenoid Synthesis

AbstractThe substituted isoborneols 1a–1g and 5,6‐dehydroisoborneols 6a–6c, readily prepared in excellent yields from (+)‐camphor and (+)‐5,6‐dehydrocamphor (2) by aryl, vinyl, or alkyl Grignard addition in the presence of stoichiometric amounts of CeCl3, were thermally isomerized in a flow reactor system under DGPTI (dynamic gas‐phase thermo‐isomerization) conditions at temperatures between 480 and 630° to give the enantiomerically pure monocyclic carbonyl compounds 7a–7d, 19a, b, 23, and 24. In all cases, product formation proceeded highly regio‐ as well as stereoselectively. The absolute configurations of the new stereogenic centers were determined by 1H‐NOE measurements. DGPTI of the aryl substrates 1a–1d is proposed to effect initial cleavage of the weakest single bond in the molecule under formation of a diradical intermediate state followed by intramolecular H‐abstraction to afford the acetophenone derivatives 7a–7d. This reaction path was further supported by a 2H‐labeling study showing the OH group to be the exclusive H‐source. In contrast, DGPTI of the vinyl substrates 1e and 6b allowed concerted retro‐ene and oxy‐Cope rearrangements. In the case of 5,6‐dehydro‐2‐phenylisoborneol (6a), concomitant diradical and retro‐Diels–Alder reaction pathways could be observed. In addition, a new route to (+)‐trans‐α‐campholanic acid (9) and (+)‐trans‐α‐dihydrocampholytic acid (14) is presented by regioselective Baeyer–Villiger oxidation and subsequent hydrolysis of 7c and 7d, respectively.