Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).     

Synthesis and characterization of novel intramolecularly O,C,O-coordinated heteroleptic organostannylenes and their tungstenpentacarbonyl complexes

The syntheses are reported of the novel heteroleptic organostannylenes [2,6-(ROCH₂)₂C₆H₃]SnCl (1, R = Me; 2, R = t-Bu) and of their tungstenpentacarbonyl complexes [2,6-(ROCH₂)₂C₆H₃](X)SnW(CO)₅ (3, X = Cl, R = Me; 4, X = Cl, R = t-Bu; 5, X = H, R = Me). The compounds were characterized by means of elemental analyses, ¹H, ¹³C, ¹¹⁹Sn NMR spectroscopies, electrospray mass spectrometry and in case of 3 and 4 also by single crystal X-ray diffraction analysis. For the two latter compounds the substituents bound at the ether oxygen atom control the strength of intramolecular O → Sn coordination. Thus, the O–Sn distances amount to 2.391(5)/2.389(5) (3) and 2.464(3)/2.513(3) Å (4).     

Synthesis,method optimization,anticancer activity of 2,3,7-trisubstituted Quinazoline derivatives and targeting EGFR-tyrosine kinase by rational approach: 1st Cancer Update

A novel 3-(substituted benzylideneamino)-7-chloro-2-phenyl quinazoline-4(3H)-one (7–27) has been synthesized and characterised by IR, ¹H NMR, ¹³C NMR spectroscopy, and elemental analysis. We changed the methodology for the synthesis of 3-amino 7-chloro-2-phenyl quinazolin-4(3H)-one 6 to fusion reaction at 250 °C, instead of using solvent, to avoid the problem of ring opening, which is commonly observed while synthesizing quinazolines from benzoxazinone. NCI selected, 7-chloro-3-{[(4-chlorophenyl) methylidene] amino}-2-phenylquinazolin-4(3H)-one 12, with GI₅₀ value of ?5.59 M, TGI value of ?5.12 M, and LC₅₀ value of ?4.40 M showed remarkable activity against CNS SNB-75 Cancer cell line. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for 2,3,7-tri substituted quinazoline derivatives to inhibit EGFR-tyrosine kinase as antitumor agents and could be used as an excellent framework in this field that may lead to discovery of potent anti tumor agent.     

Synthesis of palladium–biscarbene complexes derived from 1,1′-methylenebis(1,2,4-triazole) functionalized in the methylene bridge

Palladium–biscarbene complexes derived from N,N′-bis(1,2,4-triazol-1-yl)methane, which bear an alkyl chain functionalized with a hydroxyl group, have been synthesized ([Pd(L1)Br₂] (6) and [Pd(L1)I₂] (7) [L1 = 1,1′-(3-hydroxypropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)]). Each product is obtained as a non-equimolecular mixture of two conformers. The hydroxyl group has been replaced by bromide and methanesulphonate and ( [Pd(L2)Br₂] [L2 = 1,1′-(3-bromopropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (9)) and ([Pd(L3)Br₂] [L3 = 1,1′-(3-methanesulphonyloxypropylidene)-bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (10)) were obtained, respectively, as mixtures of conformers. All compounds consist of a six-membered metallacyclic structure in a boat conformation. Major conformers present the functionalized chain in the axial position, while in minor conformers it is located in the equatorial position.     

Novel N-substituted-5-phenyl-1H-pyrazole-4-ethyl carboxylates as potential NLO materials

In the present investigation we have synthesized a novel series of N-substituted-5-phenyl-1H-pyrazole-4-ethyl carboxylates, which are characterized by ¹H NMR, UV–Vis and FT-IR spectroscopy methods. The optical nonlinearity of the compounds in chloroform solution has been studied at 532 nm using 5 ns laser pulses, employing the open-aperture z-scan technique. It is found that compound 3c having carboxylic acid group and ester substituent has maximum nonlinearity. From measurements we conclude that compounds 3c (4-[4-(ethoxycarbonyl)-5-phenyl-1H-pyrazol-1-yl]benzoic acid) and 3e (ethyl 1-(2-bromophenyl)-5-phenyl-1H-pyrazole-4-carboxylate) are potential candidates for optical limiting applications.     

Design,synthesis and biological evaluation of quinazolin-4(3H)-one Schiff base conjugates as potential antiamoebic agents

In an effort to develop novel antiamoebic scaffolds having better efficacy than the standard drug metronidazole (IC₅₀ = 1.80 μM) used against Entamoeba histolytica, quinazolin-4(3H)-one Schiff base conjugates were synthesized and evaluated against HM1: IMSS strain of E. histolytica. Out of the thirteen compounds (S2-S14), six compounds (S2, S3, S4, S5, S6 and S11) were found to be better inhibitors than metronidazole and showed low cytotoxicity on HeLa cells, a cervical cancer cell line. The structure of intermediate compound S1 was confirmed by crystal structure studies.     

Preparation of various enantiomerically pure (benzotriazol-1-yl)- and (benzotriazol-2-yl)-alkan-2-ols

(S)-(−)-(Benzotriazol-1-yl)- and (S)-(−)-(benzotriazol-2-yl)-alkan-2-ols 7a–9a, 7b–9b and their (R)-(+)-acetates 10a–12a and 10b–12b were prepared in high enantiomeric excess via lipase from Pseudomonas fluorescens (Amano AK) catalyzed enantioselective acetylation of racemic alcohols 4a–6a and 4b–6b with vinyl acetate in tert-butyl methyl ether or toluene at 23 °C. The enantioselectivity of this transformation was dependent on the length of the alkyl chain with E-values ranging from 30 to 57. Several benzotriazole substituted ketones 1a–3a and 1b–3b were synthesized from 1H-benzotriazole and corresponding haloketones. These compounds were stereoselectively reduced with Baker’s yeast in water or in organic solvent containing 5% v/v of water at 30 °C to give the (S)-(−)-alcohol. Better stereoselectivity was observed in the kinetic resolution of racemic alcohols 4a–6a and 4b–6b (ee = 69–92% at 44–52% conversion) compared to reduction of corresponding prochiral ketones 1a–3a and 1b–3b with Baker’s yeast (ee = 40–67% at 39–89% conversion). Enhanced enantioselectivities were observed at lower temperatures.     

Synthesis,spectroscopy, electrochemistry and in situ spectroelectrochemistry of partly halogenated coumarin phthalonitrile and corresponding metal-free,cobalt and zinc phthalocyanines

In this study, the preparation of novel 7-hydroxy-3-(2-chloro-4-fluorophenyl)coumarin (1), the ligand, 7-(3,4-dicyanophenoxy)-3-(2-chloro-4-fluorophenyl)coumarin (2), metal-free phthalocyanine 3 and metallophthalocyanine complexes 4 and 5 (MPcs, M = Co, Zn), β-substituted with 7-oxo-3-(2-chloro-4-fluorophenyl)coumarin functional group was achieved. By the reaction of 7-hydroxy-3-(2-chloro-4-fluorophenyl)coumarin (1) with 1,2-dicyano-4-nitrobenzen in dry DMF as the solvent in the presence of K₂CO₃ as the base, the 7-(3,4-dicyanophenoxy)-3-(2-chloro-4-fluorophenyl)coumarin (2) was synthesized. Compound 2 reacted with Co(CH₃COO)₂·4H₂O in 2-N,N-dimethylaminoethanol to furnish a novel coumarin containing cobalt(II) phthalocyanine 4. The cyclotetramerization of 2 with Zn(CH₃COO)₂·2H₂O in 2-N,N-dimethylaminoethanol gave the novel coumarin containing Zn(II)phthalocyanine 5; while tetramerization without any metal salts in 2-N,N-dimethylaminoethanol gave the metal-free phthalocyanine 3. The structures of obtained compounds were confirmed by elemental analysis, UV–Vis, IR, MALDI-TOF mass and ¹H NMR spectra. The cyclic and differential pulse voltammetry, and in situ spectroelectrochemistry of 7-oxo-3-(2-chloro-4-fuorophenyl)coumarin substituted phthalocyanines 3, 4 and 5 allowed us to identify metal- and phthalocyanine ring-based redox processes of the complexes.     

Syntheses,structures and magnetic studies of three heterometallic Fe2Ln 1D coordination polymers

Three new heterometallic 1D coordination polymers [Fe^III₂Pr(4-Me-sal)₄(2,2′-bipy)₂(H₂O)₆](NO₃) · 2MeOH · 1.5H₂O (1), [Fe^III₂Gd(4-Me-sal)₄(2,2′-bipy)₂(H₂O)₅]Cl_1/2(NO₃)_1/2 · 5H₂O (2) and [Fe^III₂Dy(4-Me-sal)₄(2,2′-bipy)₂(H₂O)₅]Cl_1/2(NO₃)_1/2 · 5H₂O (3) have been synthesized. 1 and 2 were characterized by single-crystal X-ray crystallography, and 3 was shown to be isomorphous to 2 by X-ray powder diffraction. Magnetic studies show that the three compounds show a similar temperature dependence of their magnetic susceptibilities over the range 1.8–300 K. The observed decrease of χT with decreasing temperature for all three compounds could be the result of antiferromagnetic interactions between Fe–Ln centres and/or the depopulation of the Stark sublevels in the case of the anisotropic Ln ions (Pr^III and Dy^III).     

Design, synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds.The structures were confirmed by ~1H NMR and MS.Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro.Three of compounds (1e,1g,and 1h) exhibited potent antiproliferative activities,especially compound 1h (with IC_(50) values of 5.2μmol/L and 1.9μmol/L against Bel-7402 and HT-1080,respectively).The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.     

Dimeric and monomeric palladium(II) parent-amido (NH2) complexes: Synthesis,characterization, and reactivity

The treatment of [PdL₃(NH₃)]OTf (L₃ = (PEt₃)₂(Ph) (1), (2,6-(Cy₂PCH₂)₂C₆H₃) (3)) with NaNH₂ in THF afforded dimeric and monomeric parent-amido palladium(II) complexes with bridging and terminal NH₂, respectively, anti-[Pd(PEt₃)(Ph)(μ-NH₂)]₂ (2) and Pd(2,6-(Cy₂PCH₂)₂C₆H₃)(NH₂) (4). The dimeric complex 2 crystallizes in the space group P2₁/n with a = 13.228(2) Å, b = 18.132(2) Å, c = 24.745(2) Å, β = 101.41(1)°, and Z = 4. It has been found that there are two crystallographically independent molecules with Pd(1)–Pd(2) and Pd(3)–Pd(4) distances of 2.9594 (10) and 2.9401(9) Å, respectively. The monomeric amido complex 4 protonates from trace amounts of water to give the cationic ammine species [Pd(2,6-(Cy₂PCH₂)₂C₆H₃)(NH₃)]⁺. Complex 4 reacts with diphenyliodonium triflate ([Ph₂I]OTf) to give aniline complex [Pd(2,6-(Cy₂PCH₂)₂C₆H₃)(NH₂Ph)]OTf (5). Reaction of 4 with dialkyl acetylenedicarboxylate (DMAD, DEAD) yields diastereospecific palladium(II) vinyl derivative (Z)–(Pd(Cy₂PCH₂)₂C₆H₃)(CR = CR(NH₂)) (R = CO₂Me (6a), CO₂Et (6b)). Reacting complexes 6a and 6b with p-nitrophenol produces (Pd(Cy₂PCH₂)₂C₆H₃)(OC₆H₄–p-NO₂) (8) and cis-CHR = CR(NH₂), exclusively.     

Novel Fe (III) heterochelates: Synthesis,structural features and fluorescence studies

Fluorescence properties of five 4-acyl pyrazolone based hydrazides (H₂SB_n) and their Fe (III) heterochelates of the type [Fe(SB_n)(L)(H₂O)]·mH₂O [H₂SB_n = nicotinic acid [1-(3-methyl-5-oxo-1-phenyl-4,5-di hydro-1H-pyrazol-4yl)-acylidene]-hydrazide; where acyl = –CH₃, m = 4 (H₂SB₁); –C₆H₅, m = 2 (H₂SB₂); –CH₂–CH₃, m = 3 (H₂SB₃); –CH₂–CH₂–CH₃, m = 1.5 (H₂SB₄); –CH₂–C₆H₅, m = 1.5 (H₂SB₅) and HL = 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid] were studied at room temperature. The fluorescence spectra of heterochelates show red shift, which may be due to the chelation by the ligands to the metal ion. It enhances ligand ability to accept electrons and decreases the electron transition energy. The kinetic parameters such as order of reaction (n), energy of activation (E_a), entropy (S*), pre-exponential factor (A), enthalpy (H*) and Gibbs free energy (G*) have been reported.     

New α,ω-dicarboxylate coordination polymers with 4,4′-bipyridine: Cu(bpy)(C5H6O4), Zn(bpy)(C5H6O4), Zn(bpy)(C6H8O4) and Mn(bpy)(C8H12O4) · H2O

Four 4,4′-bipyridine α,ω-dicarboxylate coordination polymers Cu(bpy)(C₅H₆O₄) (1), Zn(bpy)(C₅H₆O₄) (2), Zn(bpy)(C₆H₈O₄) (3) and Mn(bpy)(C₈H₁₂O₄) · H₂O (4) have been synthesized and structurally characterized by single crystal X-ray diffraction methods (bpy = 4,4-bipyridine, (C₅H₆O₄)²⁻ = glutarate anion, (C₆H₈O₄)²⁻ = adipate anion, (C₈H₁₂O₄)²⁻ = suberate anion). Their crystal structures are featured by dimeric metal units, which are co-bridged by 4,4′-bipyridine ligands and dicarboxylate anions such as glutarate, adipate and suberate anions to generate 2D layers with a (4,4) topology in 1, 2 and 4 as well as to form 3D frameworks in 3. Two 3D frameworks in 3 interpenetrate with each other to form a topology identical to the well-known Nb₆F₁₅ cluster compound. Over 5–300 K, the paramagnetic behavior of 4 follows the Curie–Weiss law χ_m(T − Θ) = 4.265(5) cm³ mol⁻¹ with the Weiss constant Θ = −6.3(2) K. Furthermore, the thermal behavior of 3 and 4 is also discussed.     

Synthesis,biological evaluation and Structure Activity Relationships (SARs) study of 8-(substituted)aryloxycaffeine

A series of 8-(substituted)aryloxycaffeine were prepared from 8-bromocaffeine and (substituted)phenols by modified Ullmann reaction. In vitro antibacterial activity, inhibitory activity on topoisomerase II and pharmacological activities were evaluated for the synthesized 8-(substituted)aryloxycaffeine. Among the synthesized compounds, 8-(5-chloropyridin-3-yloxy)caffeine (3k) showed strong inhibitory activity (MIC = 15.6 μg/mL) against the tested gram negative (−) bacteria Salmonella enteritidis. 8-(quinolin-8-yloxy)caffeine (3g) showed the strongest inhibitory activity against topoisomerase II. And the compounds 8-(6-methylpyridin-2-yloxy)caffeine (3j) and 8-(3-chloro-6-(trifluoromethyl)pyridin-2-yloxy)caffeine (3m) showed analgesic effect without the central nervous system stimulation.     

Synthesis and molecular modeling study of Cu(Ⅱ) complexes derived from 2-(diphenylmethylene)hydrazinecarbothioamide derivatives with cholinesterase inhibitory activities

Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone（L¹-L⁴） have been synthesized and their Cu（Ⅱ） complexes（1-4） were afforded via coordination with cupric chloride.All these compounds were characterized by UV-vis and IR spectroscopy together with CHN elemental analysis.NMR spectroscopy was also applied to characterize the ligands.In vitro chohnesterase inhibitory assays for the complexes（1-4） showed IC₅₀ values less than 10μmol/L,with complex 1 exhibiting the most activity,IC₅₀=2.15μmol/L and 2.16μmol/L for AChE and BuChE,respectively. Molecular modeling simulation revealed the binding interaction template for complex 1 with the AChE and BuChE receptors.In DPPH assay,the complexes also showed more in vitro antioxidant activities in comparison to their parent ligands.     

Anticancer and antimicrobial evaluation of newly synthesized steroidal 5,6 fused benzothiazines

A series of new 5α-cholestano [5,6-b] benzothiazines (4–6) has been synthesized by the reaction of 5α-cholestan-6-one (1–3) with 2-aminothiophenol in the presence of iodine. The structures of newly synthesized compounds have been established on the basis of spectral and analytical data. Compounds (1–6) were screened for in vitro anticancer activity against the human cancer cell lines; SW480 (colon adenocarcinoma cells), A549 (lung carcinoma cells), HepG2 (hepatic carcinoma cells) and HeLa (cervical cancer cells) using MTT assay during which the products (4–6) showed marked increase in anticancer activity and in particular, compound 6 showed IC₅₀ = 13.73 μmol L⁻¹ against HeLa cells, being more effective than Doxorubicin against the same cells. Compounds 4 and 6 also showed minimum IC₅₀ of 15.83 μmol L⁻¹ and 16.89 μmol L⁻¹ against HepG2 and A549 cells, respectively. Compounds (1–6) were also tested for in vitro antimicrobial activity against different bacterial as well as fungal strains during which newly synthesized compounds (4–6) were found more potent than starting compounds (1–3). Compound 4 was found to be more potent than the reference drug, Chloramphenicol, in the case of Escherichia coli while compound 5 was found almost equally potential antifungal agent against P. marneffei in comparison with the reference drug, Nystatin.     

Synthesis,characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study

Two series of novel bis(indole) analogues viz., N′-((5-substituted-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)alkanehydrazides (7a–f) and N′-((5-substituted-1-(3-methylbut-2-enyl)-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)acetohydrazide (8a–f) were synthesized and characterized by spectral analysis. The target molecules were screened for their antimicrobial, anticancer activities and structure and activity relationship (SAR) was investigated. Compounds 7a, 7c and 8a were found to be active in antimicrobial screening. Anticancer screening reveals that Compound 7c was active against HeLa cell line with an IC₅₀ of 43.1 μM and compound 7d was found to be interesting candidate with an IC₅₀ of 26.0 and 30.2 μM against Colo-205 and Hep G2 cell lines respectively.     

1,3-Dipolar cycloaddition of nitrile oxides to (R)-1-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis and antimycobacterial evaluation of novel enantiomerically pure di- and trispiroheterocycles

Enantiomerically pure (R)-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones were synthesized for the first time, and their 1,3-dipolar cycloaddition with nitrile oxides affording di- and trispiroheterocycles regio- and stereoselectively in moderate yields was investigated. These compounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant M. tuberculosis (MDR-TB). Among the compounds screened, the dispiroheterocycle, namely, (5R,6R,10S)-3,9-bis(4-chlorophenyl)-10-(2,4-dichlorophenyl)-14-[(E)-(2,4-dichlorophenyl)methylidene]-12-[(R)-1-phenylethyl]-1,4,7-trioxa-2,8,12-tri-azadispiro[4.0.4.4]tetradeca-2,8-diene 5m was found to possess the maximum activity with MIC of 0.49 μM against MTB, being 9.6 and 15.6 times more potent than ciprofloxacin and ethambutol, respectively. Against MDR-TB, 5m displayed maximum activity with an MIC of 0.49 μM, with it thus being more active than rifampicin, isoniazid, ciprofloxacin and ethambutol by 7.8, 23, 77 and 124 times, respectively.     

A new molecular building blocks: Synthesis,crystal structure,magnetic and spectroscopic properties of Cu(II) and Ni(II) macrocyclic complexes

New higly unsaturated macrocyclic building blocks [CuLSCN]·ClO₄ (1) (L = N-dl-5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene) and [NiL(SCN)₂] (2) (L = N-dl-5,12-dimethyl-7,14-diisopropyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene) were synthesized and the crystal structures of both compounds were determined. Both complexes crystallizes in monoclinic, space group P2₁/n (1) and P2₁/c (2). Their magnetic properties were studied over the temperature range 1.8–300 K using a Quantum Design SQUID magnetometer (MPMSXL-5-type). The results indicate that both compounds behave as weakly interacting paramagnetic centers in the crystal lattice. The effects of hydrogen bond mediating the magnetic exchange interactions on the spin density have been evidenced by DFT calculations. The NIR–Vis–UV diffuse-reflectance electronic spectra confirm the square pyramidal and octahedral geometry around Cu²⁺ and Ni²⁺ metal ions.     

Lewis acid-assisted olefin cross-metathesis reaction: an efficient approach for the synthesis of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin and evaluation of their antitumor activity

A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a–g) were synthesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OⁱPr)₄ 30 mol % and 10 mol % of Grubb’s second generation catalyst with good to excellent yields. Most of these compounds exhibited significant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e) showed potent cytotoxic activity.