Synthesis and biological evaluation of new pyrazolebenzene-sulphonamides as potential anticancer agents and hCA I and II inhibitors

Cancer is a disease characterized by the continuous growth of cells without adherence to the rules that healthy normal cells obey. Carbonic anhydrase I and II (CA I and CA II) inhibitors are used for the treatment of some diseases. The available drugs in the market have limitations or side effects, which bring about the need to develop new drug candidate compound(s) to overcome the problems at issue. In this study, new pyrazole-sulphonamide hybrid compounds 4-[5-(1,3-benzodioxol-5-yl)-3-aryl-4,5-dihydro-1 H -pyrazol-1-yl]benzenesulphonamides (4a - 4j) were designed to discover new drug candidate compounds. The compounds 4a - 4j were synthesized and their chemical structures were confirmed using spectral techniques. The hypothesis tested was whether an introduction of methoxy and polymethoxy group(s) lead to an increased potency selectivity expression (PSE) value of the compound, which reflects cytotoxicity and selectivity of the compounds. The cytotoxicity of the compounds towards tumor cell lines were in the range of 6.7 – 400 µM. The compounds 4i (PSE₂ = 461.5) and 4g (PSE₁ = 193.2) had the highest PSE values in cytotoxicity assays. Ki values of the compounds were in the range of 59.8 ± 3.0 - 12.7 ± 1.7 nM towards hCA I and in the range of 24.1 ± 7.1 - 6.9 ± 1.5 nM towards hCA II. While the compounds 4b, 4f, 4g, and 4i showed promising cytotoxic effects, the compounds 4c and 4g had the inhibitory potency towards hCA I and hCA II, respectively. These compounds can be considered as lead compounds for further research.     

New liquid crystal compounds ( )-4-[5-(2-Methylbutyl)-1,3-dioxan-2-yl]phenyl 4-alkoxybenzoate

New liquid crystal compounds, (+)-4-[5-(2-methylbutyl)-1,3-dioxan-2-yl] phenyl 4-alkoxybenzoates (5), were synthesized. The mesomorphic behaviour of these compounds is compared with that of (+)-4-(5-alkyl-1,3-dioxan-2-yl)-phenyl 4-(2-methylbutoxy)benzoates (6). While compounds 6 exhibited a chiral smectic C phase, the corresponding compounds 5 did not. This might mean that for the appearance of a chiral smectic C phase in these types of compounds, it is necessary that the carbonyl and the chiral groups exist at nearby positions. Transition temperatures to those isotropic state for compounds 5 were lower than those for compounds 6. This result is common in both cases of (+)-4-alkoxycarbonylphenyl-4-[5-(2-methylbutyl)-1,3-dioxan-2-yl]benzoates (7), and (+)-4-(2-methylbutoxy-carbonyl)phenyl 4-(5-alkyl-1,3-dioxan-2-yl)-benzoates (8).     

2-Amino-3-cyano-4H-chromene-4-ylphosphonates as potential antiviral agents: Synthesis,in ovo and in silico approach

A simplistic synthetic procedure for the synthesis of structurally diversified 2-amino-3-cyano-4H-chromene-4-ylphosphonates ( 4a-j ) were developed by the treatment of substituted salicylaldehydes, malononitrile, and dialkyl phosphite in presence of Cu(OAc)₂ catalyst at room temperature and neat conditions. The synthesized compounds were tested for their antiviral assay. Among all, the compounds 4a , 4d and 4h have shown good in ovo antiviral activity against New castle disease virus (NDV) at a concentration of 150 μg/mL. The remarkable reduction in NDV virus population in embryos treated with title compounds ( 4a-j ) in a dose dependent manner, indicated that the synthesized compounds are extreme by toxic to the NDV virus. The title compounds were also docked against hemagglutinin neuraminidase enzyme and the more bioactive compound 4a showed highest docking score than the standard antiviral drug taribavirin while the compounds 4d and 4h has the same docking score as that of the standard.     

Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies

In a single reaction step, pyrimidine derivatives ( 4a-p ) were synthesized from the triple reaction of aromatic aldehydes ( 1) , ethyl cyanoacetate ( 2) , and some guanyl hydrazone derivatives (3a-n) . These compounds were tested as in vitro against two types of cancerous cell lines, namely, a human colon cancerous cell line (DLD-1) and a human breast cancerous cell line (MDA-MB-231). According to the obtained results, nearly all the compounds have cytotoxic activity in the tested cell lines. Especially, the compounds 4j , 4k , and 4n had a significant effect against DLD-1. Furthermore, compounds 4g , 4m , and 4o exhibited lower IC₅₀ values compared to other synthesized compounds against MDA-MB-231. We hope that these compounds can be improved as anticancer agents in the future. Molecular docking was performed according to both topoisomerase I and N-acetyltransferase 1 proteins to examine theoretically the binding mode and site of pyrimidine compounds having the best activity.     

Synthesis and Biological Activity of 3-[4H-(1,2,4)-Triazolyl]-2,6-diaryl-1,3,5-oxadiazine-4-thione

4-Amino-1,2,4-triazole (1) undergoes facile condensation with aromatic aldehydes to afford the corresponding 4-(arylidene-amino)-4H-[1,2,4]-triazole (2a–h) in good yield. Rearrangement of compounds (2a–h) with benzoyl isothiocyanate/4-chloro-benzoyl isothiocyanate/2,4-dichloro-benzoyl isothiocyanate yields corresponding 1,3,5-oxadiazine derivatives (3). Structural elucidation of these compounds was based on elementary analysis and spectral data studies. The newly synthesized compounds were evaluated for their antibacterial activities.     

A μ(1,1)- or μ(1,3)-carboxylate bridge makes the difference in the magnetic properties of dinuclear Mn(II) compounds

Six new dinuclear Mn(II) compounds with carboxylate bridges have been synthesized and characterized by X-ray diffraction: [{Mn(phen)(2)}(2)(μ-RC(6)H(4)COO)(2)](ClO(4))(2) with R = 2-Cl (1), 2-CH(3) (2), 3-Cl (3), 3-CH(3) (4), 4-Cl (5) and 4-CH(3) (6). Compounds 1 and 2 show two μ(1,3)-carboxylate bridges in a syn-anti mode while compounds 3-6 present a very uncommon coordination mode of the carboxylate ligand: the μ(1,1)-bridge. The magnetic properties of these compounds are very sensitive to the bridging mode of the carboxylate ligands. While compounds 1 and 2 (μ(1,3)-bridge) display antiferromagnetic interactions, with J values of -1.41 and -1.66 cm(-1), respectively, compounds 3-6 (μ(1,1)-bridge) show ferromagnetic interactions, with J values of 1.01, 0.98, 1.04 and 1.06 cm(-1), respectively. It is worth noting that compounds 3-6 are the first of their class to be magnetically characterized. The EPR spectra at 4 K for compounds with antiferromagnetic coupling (1 and 2) are more complex than those for compounds with a ferromagnetic interaction (3-6). Quite good simulations can be obtained with the ZFS parameters of the Mn(II) ion D(Mn) ~ 0.095 cm(-1) and E(Mn) ~ 0.025 cm(-1) for compounds 1 and 2 and D(Mn) ~ 0.060 cm(-1) and E(Mn) ~ 0.004 cm(-1) for compounds 3-6.     

Highly selective colorimetric and electrochemical Pb2+ detection based on TTF-pi-pyridine derivatives

[reaction: see text] The pyridineethenyl-substituted tetrathiafulvalene (TTF) compounds, 4-(4-pyridineethenyl)tetrathiafulvalene (1a) and 4,4'(5')-[bis-(4-pyridineethenyl)]tetrathiafulvalene (2a) together with the styryl-substituted TTF compounds, 4-styryltetrathiafulvalene (1b) and 4,4'(5')-bis-styryltetrathiafulvalene (2b), have been designed and synthesized. All these compounds exhibit strong absorption bands in the range of 370 to 550 nm, which are assigned to the intramolecular charge-transfer transition from the HOMO in TTF to the LUMO in the pyridyl or phenyl group. Compared to compounds 1b and 2b, the pyridineethenyl-substituted TTF compounds 1a and 2a show remarkable sensing and coordinating properties to Pb2+. With the addition of micromolar concentrations of Pb2+ to the solution, 1a or 2a displays dramatic changes in the UV-vis absorption spectrum, 1H NMR spectrum, and redox property.     

Synthesis and Anti‐inflammatory Screening of Some Mono and Bis‐Alkoxyphthalimide Linked Benzimidazole and their Quinazoline and Pyrimidine Derivatives

In the present study, synthesis of some nonsymmetrical 2‐(1H‐benzimidazol‐2‐ylamino)‐7,7‐dimethyl‐7,8‐dihydroquinazolin‐5(6H)‐one ( 3 ) and substituted‐(1H‐benzo[d]imidazol‐2‐yl)amino‐pyrimidine derivatives ( 4a , 4b , 4c and 5a , 5b ) is described as a three‐component reaction of 2‐guanidinobenzimidazole ( 2 ) with triethyl orthoformate and different reactive methylene compounds. Subsequent condensation of compounds 3 , 4a , 4b , 4c , and 5a , 5b with bromoethoxyphthalimide ( 1 ) gave final compounds 6 , 7a , 7b , 7c , and 8a , 8b . Synthesized final compounds have been screened for their in‐vivo anti‐inflammatory activity against carrageenan‐induced paw edema in albino rats. Diclofenac was used as standard anti‐inflammatory agents. Some of the compounds exhibited significant anti‐inflammatory activity, as compared to standard drug. Structures of synthesized compounds have been confirmed on the basis of chemical tests and spectral studies.     

Studies on Organophosphorus Compounds: Synthesis and Reactions of Some New 5′-Cyano-2′-(4-methoxyphenyl)spiro[cycloalkane-1,6′-[1,3,2]thiazaphosphixane]-2′,4′-disulfide Derivatives

2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent, LR, 1 ) reacts with cycloalkylidenecyanothioacetamides ( 2 and 3 ) to give 5'-cyano-2'-(4-methoxyphenyl)spiro [cyclopentane(cyclohexane)-1,6'-perhydro-[1,3,2]thiazaphosphixane]-2',4'-disulfide ( 4 and 5 ). The reaction of compounds 4 and 5 with f -halo compounds led to the formation of the substituted thio-compounds 6a-e and 7a-e , respectively, these compounds, upon treatment with sodium ethoxide, produce the corresponding thienothiazaphosphixine derivatives 8a-e and 9a-e respectively. Compounds 8a-e and 9a-e react with LR under different reaction conditions to give polyfused heterocyclic compounds 10a-d and 11a-d respectively. Treatment of compounds 8b and 9b with CS 2 and (CH 3 ) 2 SO 4 gave the corresponding dithiocarbamate methyl ester derivatives 12 and 13 , respectively, which on treating with hydrazine hydrate yielded compounds 14 and 15 respectively. Compounds 14 and 15 reacted with LR to yield compounds 16a , b and 17a , b respectively.     

Syntheses, structures, and nonlinear optical properties of heteroselenometallic W-Se-Ag cluster compounds containing phosphine ligands

Treatment of [Et4N]2[WSe4] with a 1:1 mixture of AgNO3 and PCy3 (Cy = cyclohexyl) in the absence of iodide afforded a linear trinuclear compound [(mu-WSe4)(AgPCy3)2] (1). A similar reaction in the presence of iodide gave rise to the isolation of the cubanelike compound [(mu3-WSe4)Ag3(PCy3)3(mu3-I)] (2). Treatment of [Et4N]2[WSe4] with AgI in the presence of bidentate phosphine ligands bis(diphenylphosphino)amine (dppa) and bis(diphenylphosphino)methane (dppm) afforded the tetranuclear compounds [(mu3-WSe4)Ag3(mu-I)(mu-dppa)2] (3) and [(mu3-WSe4)Ag3(mu3-I)(mu-dppm)2] (4), respectively, which exhibit an open butterfly configuration. A novel hexanuclear cluster compound [(mu3-WSe4)2Ag4(mu-dppm)3] (5) was obtained from interaction of [Et4N]2[WSe4] with AgNO3 and dppm in the absence of iodide source. The above cluster compounds are electrically neutral and air-stable in both solution and the solid state and have been characterized by electronic, infrared, mass, and NMR spectroscopies. The solid-state structures of five cluster compounds have been established by X-ray crystallography. The nonlinear optical properties of compounds 4 and 5 were examined by z-scan techniques with 7 ns pulses at 532 nm. The optical limiting effects of compounds 1, 2, 4, and 5 were determined and compared with related argentoselenometallic compounds.     

Ge4Br4[Mn(CO)5]4 and Ge6Br2[Mn(CO)5]6: first germanium cluster compounds containing Mn(CO)5 ligands

Cluster compounds of germanium exhibiting germanium-germanium bonds, where the germanium atoms are additionally bound to transition metal ligands, are rare. Here a synthetic pathway to such cluster compounds is described, starting from metastable Ge I halide solutions leading to the two cluster compounds Ge4Br4[Mn(CO)5]4 and Ge6Br2[Mn(CO)5]6, being the first examples of germanium cluster compounds bearing Mn(CO)5 ligands. The Ge6 compound exhibits a novel arrangement of germanium atoms that has not been previously observed in ligand stabilized cluster compounds of germanium, neither with organic nor with transition metal ligands. The bonding situation inside the cluster compounds is discussed, together with a possible reaction pathway that opens the way to metalloid cluster compounds of germanium exhibiting Mn(CO)5 ligands.     

Synthesis and search for compounds with hemostatic activity in the series of 4-(het)aryl-4-oxobut-2-enoic acid derivatives

New 4-aryl-2-(4-arylamino)-1-(piperazin-1-yl)but-2-ene-1,4-diones and 2-{[2-(3-R-adamantan-1-yl)-2-oxoethylidene]hydrazinyl}-4-(het)aryl-4-oxobut-2-enoic acids were synthesized and used to obtain water-soluble compounds. Their influence on the blood coagulation system was studied, which revealed compounds with a high hemostatic activity and a low acute toxicity. A relationship between structure and pharmacological effect of the synthesized compounds was established.     

Noncovalent complexes of water-soluble polymers and organoplatinum compounds as potential time-release antitumor agents

The complexation of appropriate organoplatinum compounds by water-soluble polymers has the potential to provide a time-release formulation which might afford a substantial reduction in the severity of side effects associated with use of organoplatinum antitumor agents. Both poly-(N-vinylpyrrolidone)(PVP) and poly(N-vinyl-5-methyl-2-oxazolidone)(PVOM) form stable, biologically active, molecular complexes with organoplatinum compounds containing polar aromatic ligands. Platinum compounds suitable for complexation by these polymers include cis-dichloro(4-substituted o-phenylenediamine)platinum(II), 4-substitutedcatecholato(1,2-diaminocyclohexane)platinum(II), and 4-substitutedphthallato(1,2-diaminocyclohexane)-platinum(II) compounds.     

Cyano- and Nitro-containing Compounds from the Roots of Semiaquilegia adoxoides

Four cyano-containing compounds, (1E,4α,5β,6α)-4,5,6-trihydroxy-2-cyclohexen-l-ylideneacetonitrile (1), lithospermoside (2), 4-hydroxy-2-β-D-glucopyranosyl oxyphenylacetonitrile (3) and 4-[β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranosyl oxy]phenylacetonitrile (4), and a nitro-containing one, 4-[β-D-xylopyranosyl-(1→6)-O-β-D-glucopyranosyloxy]-1-(2-nitroethyl)benzene (5), as well as eleven other types of compounds, were isolated from the roots of Semiaquilegia adoxoides. Their structures were elucidated mainly by spectroscopic methods. Among them, 1 and 4 are new isolated compounds. The cyano- and nitro-containing compounds are very rare in plants and their isolation from one traditional Chinese medicine is really interesting.     

2-芳基-5-(4-硝基苯甲酰氨基)-1,3,4-噻二唑的合成

以芳甲酰肼和对硝基苯甲酰氯为主要原料, 合成出了10个酰氨基硫脲化合物5a～5j, 其中有6个(5d, 5f～5j)为新化合物. 在无需任何酸性催化剂条件下, 将制得的酰氨基硫脲在DMF中加热回流直接脱水关环合成出了9个2-芳基-5-(4-硝基苯甲酰氨基)-1,3,4-噻二唑化合物6a～6i, 其中7个(6b～6d, 6f～6i)为新化合物. 利用IR和1H NMR证明了化合物5存在两种异构体. 目标产物的结构通过IR, 1H NMR和元素分析进行了表征.     

新型二氧代氮杂茂并[3’,4’-d]N-甲基异噁唑四氯化铁酸盐衍生物的合成及其生物活性

硫酸二甲酯作为N-甲基化试剂,与相应的异噁唑啉反应,并在盐酸中三氯化铁作为阴离子交换试剂,合成了15个未见文献报道的2-甲基-3-(1’,2’-二-O-环亚己基二氧乙基)-5-芳基-3a,6a-二氢-4,6-二氧代氮杂茂并[3’,4’-d]异噁唑四氯化铁酸盐衍生物4a～4o.化合物4a～4o结构结构经1H NMR,IR和元素分析确证,并进行了初步药物活性筛选,大部分化合物显示了不同程度的抗癌和抗炎症性及免疫性疾病活性.体外抗癌活性试验表明,当样品浓度为20μg/mL时,除了4h无活性外,其余化合物对细胞分裂周期磷酸酯酶Cdc25B的抑制率为≥97.55%.此外,体外白细胞共同抗原活性试验表明,当样品浓度为20μg/mL时,所有化合物4a～4o对白细胞共同抗原CD45蛋白酪氨酸磷酸酶A具有良好的抑制活性,其抑制率为68.41%～93.38%.在此基础上,初步讨论了该类化合物的构效关系.     

Synthesis, characterization, biocide and toxicological activities of di-n-butyl- and diphenyl-tin(IV)-salicyliden-beta-amino alcohol derivatives

The one pot reaction of salicylaldehyde 1, beta-amino alcohols 2a-2c, and di-n-butyltin(IV) oxide 3a or diphenyltin(IV) oxide 3b produced five diorganotin(IV) compounds, 4a-4c, 5a, and 5c, in good yields. All compounds were characterized by IR, (1)H, (13)C, and (119)Sn NMR spectroscopy, and elemental analysis; furthermore, compounds 4b, 4c, 5a, and 5c were characterized by X-ray diffraction analysis. After the structural characterization, all of the compounds were tested in vitro against Bacillus subtilis (Gram-positive, strain ATCC 6633), Escherichia coli (Gram-negative, strain DH5alpha), Pseudomonas aeruginosa (Gram-negative, strain BH3), Desulfovibrio longus (strain DSM 6739), and Desulfomicrobium aspheronum (strain DSM 5918) to assess their antimicrobial activity. Compounds 4 and 5 demonstrated a wide range of bactericidal activities against the tested aerobic (one Gram-positive and two Gram-negative subtypes) and anaerobic bacteria (two sulfate-reducing bacteria, SRB). Compound 5 had better bactericidal performances than compound 4. For all of the compounds, the acute toxicity was measured using luminescent bacteria toxicity (LBT-Microtox) tests to track their further environmental impact. According to these results and in order to fulfill environmental regulations, the toxicity of the compounds studied herein can be modulated through the proper selection of the disubstituted tin(IV) moiety.     

A Convenient and Practical Prepapation of Acetylphenyl Boronic Acids

A practical and scalable synthesis route of acetylphenylboronic acids is described. Bromoacetophenones (compounds 3a, 3b) were ketalized with ethylene glycol and triethyl orthoformate to give bromo ketals (compounds 4a-4c) in 60-80% yields. Compounds 4a-4b were treated with a Grignard reagent and then exchanged with borate to give p-and m-acetylphenyl boronic acids(compounds 5a and 5b) in 80% and 56% yields, respectively. The o-form(compound 5c) was obtained in 61% yield via the BuLi method.     

High coordination chemically bound compounds of noble gases with hydrocarbons: Ng(CCH)4 and Ng(CCH)6, (Ng=Xe or Kr)

Ab initio calculations predict the existence of the compounds Ng(-C[triple bond]CH)4 and Ng(-C[triple bond]CH)6, where Ng=Xe or Kr. Presently known organic noble gas compounds have a coordination number of two at most. The Ng(-C[triple bond]CH)(4) molecules have D(4h) symmetry, and Ng(-C[triple bond]CH)(6) molecules have O(h) symmetry. The bonding in all these compounds is partly ionic and partly covalent, with significant contributions from both types of bonding. The relatively high vibrational frequencies and the substantial Ng-(C[triple bond]CH) binding energy in these species indicate that these compounds should be fairly stable, at least in cryogenic conditions. These compounds could be a very interesting addition to the range of known organic noble gas compounds. Suggestions are made on possible approaches to their preparation.     

Synthesis,Docking and Biological Evaluation of Isoquinolonic Acid Derivatives

A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.