Design and Synthesis of Novel Thiazolo[5,4‐d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR‐2 has been demonstrated as a key method against tumor‐associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4‐d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(3,4‐dimethylphenyl)urea) and 3m (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(4‐methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC₅₀=1.65 and 3.52 μm , respectively). Compound 3l also showed the best potency against VEGFR‐2 at 50 μm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.     

Further Thymol Derivatives from Ageratina cylindrica

From the leaves of Ageratina cylindrica, in addition to the described [(2S)‐2‐{4‐formyl‐5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl]methyl benzoate (cylindrinol A, 8 ), seven new thymol derivatives were isolated and named cylindrinols B – H ( 1 – 7 ). The structures of these compounds were established as (2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 1 ), (2‐{4‐formyl‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 2 ), (2‐{4‐[(acetyloxy)methyl]‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 3 ), [2‐(2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 4 ), [2‐(5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 5 ), 2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}prop‐2‐en‐1‐yl benzoate ( 6 ), and 2‐hydroxy‐2‐[2‐hydroxy‐4‐(hydroxymethyl)‐phenyl]‐3‐[(2‐methylpropanoyl)oxy]propyl benzoate ( 7 ), by spectroscopic means. Compounds 1 showed moderate antiprotozoal activity on both protozoa. Compounds 4 and 5 showed selectivity on Giardia lamblia trophozoites. All isolated compounds were less active than two antiprotozoal drugs, metronidazole and emetine, used as positive controls. Compound 5 exhibited a high inhibitory effect on hyperpropulsive movement of the small intestine in rats; its effect was best than loperamide, antidiarrheal drug used as a positive control.     

Synthesis and Biological Evaluation of Novel Oxazolo[5,4‐d]pyrimidines as Potent VEGFR‐2 Inhibitors

Tumor angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) and other protein kinases. Inhibition of these kinases presents an attractive approach for developing anticancer therapeutics. In this work, a series of 2,5,7‐trisubstituted oxazolo[5,4‐d]pyrimidines were synthesized, and their inhibitory activities were investigated against VEGFR‐2 and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 9n exhibited the most potent inhibitory activity with IC₅₀ values of 0.33 and 0.29 μM for VEGFR‐2 kinase and HUVEC, respectively. A further kinase selectivity assay revealed that these compounds exhibit good VEGFR and moderate EGFR inhibitory activities. Docking analysis suggested a common mode of interaction at the ATP‐binding site of VEGFR‐2.     

One‐Pot Synthesis of New (1,3‐Thiazolo[5,4‐b]pyridin‐2‐yl)benzenediols and Their Antiproliferative Activities against Human Cancer Cell Lines

A one‐pot synthesis of new 4‐(1,3‐thiazolo[5,4‐b]pyridin‐2‐yl)benzene‐1,3‐diols has been described. The compounds were prepared by the reaction of sulfinylbis[(2,4‐dihydroxyphenyl)methanethione] derivatives, with various substituents in the aryl rings, with 2‐chloropyridin‐3‐amines. Their structures were deduced from IR and, ¹H‐ and ¹³C‐NMR spectroscopic, mass spectrometric, and elemental analyses. The antiproliferative properties of some of the products against human cancer cell lines were comparable to those of cisplatin. Structure? activity analysis showed that the presence of hydrophobic substituents in both heterocyclic fused and phenyl rings of the compounds improves their biological effects. Further, an additional OH group in the resorcinol moiety reduced the antiproliferative activity.     

Secolignans with antiangiogenic activities from Peperomia dindygulensis

Two new secolignans, peperomins G and H ( 1 and 2 , resp.), were isolated from the whole plant of Peperomia dindygulensis, together with five known secolignans, peperomin A ( 3 ), peperomin E ( 4 ), peperomin B ( 5 ), 2,3‐trans‐2‐methyl‐3‐{(3‐hydroxy‐4,5‐dimethoxyphenyl)[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 6 ), 2,3‐cis‐2‐(hydroxymethyl)‐3‐{bis[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 7 ). Their structures and configurations were elucidated by spectroscopic methods including 2D‐NMR techniques. Antiangiogenic effects of all compounds were evaluated using human umbilical vein endothelial cells (HUVEC) proliferation and tube‐formation tests, with compounds 4 and 5 being active in the bioassay. Compounds 4 and 5 induced obvious cell toxicity to HUVEC with IC₅₀ values of 1.64±0.19 and 8.44±0.4 μM , respectively. Compounds 4 and 5 also exhibited significant HUVEC tube formation‐inhibiting activity with IC₅₀ values of 3.13±0.09 and 6.24±0.12 μM , respectively.     

Design and Synthesis of Novel Arylisoxazole‐Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease

A novel series of hybrid arylisoxazole‐chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5‐(3‐nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC₅₀=1.23 μm ) and 5‐(3‐chlorophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC₅₀=9.71 μm ). 5‐(3‐Nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50 μm . It also showed 6.4 % protection at 25 μm and satisfactory chelating ability toward Zn²⁺, Fe²⁺, and Cu²⁺ ions. Docking studies of 5‐(3‐nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide and 5‐(3‐chlorophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.     

Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

The 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were synthesized from the reactions of 7‐benzylidenebicyclo[3.2.0]hept‐2‐en‐6‐ones with 2‐aminobenzenethiol. The antiproliferative activities of 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma cells) cell lines using BrdU cell proliferation ELISA assay. Cisplatin and 5‐fluorouracil (5‐FU) were used as standards. The most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 cell lines with IC₅₀=5.89 μm value (cisplatin, IC₅₀=14.46 μm and 5‐FU, IC₅₀=76.74 μm ). Furthermore, the most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa cell lines with IC₅₀=3.98 μm (cisplatin, IC₅₀=37.95 μm and 5‐FU, IC₅₀=46.32 μm ). Additionally, computational studies of related molecules were performed by using B3LYP/6‐31G+(d,p) level in the gas phase. Experimental IR and NMR data were compared with the calculated results and were found to be compatible with each other. Molecular electrostatic potential (MEP) maps of the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa and the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 were investigated, aiming to determine the region that the molecule is biologically active. Biological activities of mentioned molecules were investigated with molecular docking analyses. The appropriate target protein (PDB codes: 1 M17 for the HeLa cells and 1JQH for the C6 cells) was used for 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole and 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole molecules exhibiting the highest biological activity against HeLa and C6 cells in the docking studies. As a result, it was determined that these molecules are the best candidates for the anticancer drug.     

Synthesis of Novel Aryloxyethylamine Derivatives and Evaluation of Their in Vitro and in Vivo Neuroprotective Activities

A series of aryloxyethylamine derivatives were designed, synthesized and evaluated for their biological activity. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, FT‐IR and HR‐ESI‐MS. The preliminary screening of neuroprotection of compounds in vitro was detected by MTT, and the anti‐ischemic activity in vivo was tested using bilateral common carotid artery occlusion in mice. Most of these compounds showed potential neuroprotective effects against the glutamate‐induced cell death in differentiated rat pheochromocytoma cells (PC12 cells), especially for (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone, (4‐bromophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, (4‐chlorophenyl)(1‐{2‐[(naphthalen‐2‐yl)oxy]ethyl}piperidin‐4‐yl)methanone, (4‐chlorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone and {1‐[2‐(4‐bromophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, which exhibited potent protection of PC12 cells at three doses (0.1, 1.0, 10 μM). Compounds (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, (4‐fluorophenyl){1‐[2‐(naphthalen‐2‐yloxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed the significant prolongation of the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all five doses tested (200, 100, 50, 25, 12.5 mg/kg) and had significant neuroprotective activity. In addition, (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed outstanding neuroprotection in vitro and in vivo. These compounds can be used as a promising neuroprotective agents for future development of new anti‐ischemic stroke agents. Basic structure–activity relationships are also presented.     

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

A variety of 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethines and 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin‐induced seizure model. The prepared 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7‐{(E)‐[(4‐nitrophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐{(E)‐[(4‐bromo‐2,6‐difluorophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one and 7‐[(E)‐{[3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.     

A novel compound T7 (N-{4′-[(1E)-N-hydroxyethanimidoyl]-3′,5,6-trimethoxybiphenyl-3-yl}-N′-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) screened by tissue angiogenesis model and its activity evaluation on anti-angiogenesis

A tissue model for angiogenesis that imitated new blood vessels formation in vivo had been established in the previous study. Here, it was used to screen and evaluate a series of synthesized compounds and the results indicated that compound T7 (N-{4′-[(1E)-N-hydroxyethanimidoyl]-3′,5,6-trimethoxybiphenyl-3-yl}-N′-[4-(3-morpholin-4-ylpropoxy)phenyl]urea) could effectively inhibit the blood vessels formation. Then the anti-angiogenic potential of T7 and its related molecular mechanisms against lung carcinoma in vitro and in vivo were investigated. Treatment with T7 significantly inhibited human umbilical vein endothelial cells and A549 cells proliferation and migration. T7 reduced human umbilical vein endothelial cells tube formation as well. Western blotting analysis of cell signaling molecules indicated that T7 reduced phosphorylation of KDR and its downstream signaling players AKT and ERK1/2 activation in endothelial cells and A549 cells. Moreover, T7 inhibited tumor growth in A549 xenografted model of athymic mice and reduced CD34 expression levels in tumor-bearing mice by immunohistochemistry. In sum, our findings showed that T7 was a candidate of tumor angiogenesis inhibitors, and it functioned by interrupting the autophosphorylation of KDR, AKT and ERK1/2.     

Synthesis and Activity Evaluation of Nasopharyngeal Carcinoma Inhibitors Based on 6‐(Pyrimidin‐4‐yl)‐1H‐indazole

Human nasopharyngeal carcinoma is a common head and neck malignancy with high incidence in Southeast Asia and Southern China. It is necessary to develop safe, effective and inexpensive anticancer agents to improve the therapeutics of patients with nasopharyngeal carcinoma. A series of small molecular compounds based on 6‐(pyrimidin‐4‐yl)‐1H‐indazole were synthesized and evaluated for antiproliferative activities against human nasopharyngeal carcinoma cell lines SUNE1. Compounds 6b , 6c , 6e and 6l showed potent antiproliferative activities similar to positive control drug cisplatin in vitro with lower nephrotoxicity than it. N‐[4‐(1H‐Indazol‐6‐yl)pyrimidin‐2‐yl]benzene‐1,3‐diamine ( 6l ) was selected for further study. It was found that 6l induced mitochondria‐mediated apoptosis and G₂/M phase arrest in SUNE1 cells. Furthermore, compound 6l at 10 mg/kg can suppress the growth of an implanted SUNE1 xenograft with a TGI% (tumor growth inhibition) value of 50 % and did not cause serious side effects in BALB/c nude mice. This study suggests that 6‐(pyrimidin‐4‐yl)‐1H‐indazole derivatives are a series of small molecule compounds with anti‐nasopharyngeal carcinoma activities.     

Two New Pyrrolosesquiterpenes Produced by a Streptomyces Species

Two new pyrrolosesquiterpenes, 1 and 2 , were isolated from cultures of the soil actinomycete Streptomyces sp. Hd7–21. The structures of these compounds were established as (2Z,4E,9E)‐6,7,11‐trihydroxy‐3,7,11‐trimethyl‐1‐(1H‐pyrrol‐2‐yl)dodeca‐2,4,9‐trien‐1‐one ( 1 ) and (2Z,4E)‐5‐{3‐[(2E)‐4‐hydroxy‐4‐methylpent‐2‐en‐1‐yl]‐3‐methyloxiran‐2‐yl}‐3‐methyl‐1‐(1H‐pyrrol‐2‐yl)penta‐2,4‐dien‐1‐one ( 2 ) by extensive spectroscopic analyses including MS, and 1D‐ and 2D‐NMR data. Their cytotoxic activities against a panel of human cancer cell lines were evaluated.     

Synthesis and Fungicidal Activities of New 1,2,4‐Triazolo[1,5‐a]pyrimidines

A series of new acetohydrazone‐containing 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives were designed and synthesized for the purpose of searching for novel agrochemicals with higher fungicidal activity. Their in vitro fungicidal activities against Rhizoctonia solani were evaluated, and the most promising compound, 2‐[(5,7‐dimethyl[1,2,4]triazolo[1,5‐a]pyrimidin‐2‐yl)sulfanyl]‐2′‐[(2‐hydroxyphenyl)methylidene]acetohydrazide ( 2‐17 ), showed a lower EC₅₀ value (5.34 μg ml^?1) than that of commercial carbendazim (EC₅₀=7.62 μg ml^?1). Additionally, compound 2‐17 was also found to display broad‐spectrum fungicidal activities, and its EC₅₀ value (4.56 μg ml^?1) against Botrytis cinereapers was very similar to that of carbendazim. Qualitative structure–activity relationships (QSARs) of the synthesized compounds were also discussed.     

Work Function Control of Interfacial Buffer Layers for Efficient and Air‐Stable Inverted Low‐Bandgap Organic Photovoltaics

A water‐soluble cationic polythiophene derivative, poly[3‐(6‐{4‐tert‐butylpyridiniumyl}‐hexyl)thiophene‐2,5‐diyl] [P3(TBP)HT], is combined with anionic poly(3,4‐ethylenedioxythiophene):poly(p‐styrenesulfonate) (PEDOT:PSS) on indium tin oxide (ITO) substrates via electrostatic layer‐by‐layer (eLbL) assembly. By varying the number of eLbL layers, the electrode's work function is precisely controlled from 4.6 to 3.8 eV. These polymeric coatings are used as cathodic interfacial modifiers for inverted‐mode organic photovoltaics that incorporate a photoactive layer composed of either poly[(3‐hexylthiophene)‐2,5‐diyl] (P3HT) and the fullerene acceptor [6,6‐phenyl‐C₆₁‐butyric acid methyl ester (PC₆₁BM) or the low bandgap polymer [poly({4,8‐di(2‐ethylhexyloxyl)benzo[1,2‐b:4,5‐b′]dithiophene}‐2,6‐diyl)‐alt‐({5‐octylthieno[3,4‐c]pyrrole‐4,6‐dione}‐1,3‐diyl) (PBDTTPD)] and the electron acceptor [6,6‐phenyl‐C₇₁‐butyric acid methyl ester (PC₇₁BM)]. The power conversion efficiency (PCE) of the resulting photovoltaic device is dependent on the composition of the eLbL‐assembled interface and permits the fabrication of devices with efficiencies of 3.8% and 5.6% for P3HT and PBDTTPD donor polymers, respectively. Notably, these devices demonstrate significant stability with a P3HT:PC₆₁BM system maintaining 83% of its original PCE after 1 year of storage and a PBDTTPD:PC₇₁BM system maintaining 97% of its original PCE after over 1000 h of storage in air, according to the ISOS‐D‐1 shelf protocol.     

Salophen Copper(II) Complex‐Assisted Click Reactions for Fast Synthesis of 1,2,3‐Triazoles Based on Naphthalene‐1,4‐dione Scaffold,Antibacterial Evaluation,and Molecular Docking Studies

The salophen copper(II) complex was successfully used for the efficient synthesis of new 1,2,3‐triazoles based on the naphthalene‐1,4‐dione scaffold. The reaction of 2‐chloro‐3‐(prop‐2‐yn‐1‐yloxy)naphthalene‐1,4‐dione or 2,3‐bis(prop‐2‐yn‐1‐yloxy)naphthalene‐1,4‐dione with aromatic azides in the presence of a low copper catalyst (loading 1 mol‐%) afforded 2‐chloro‐3‐[(1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy]naphthalene‐1,4‐dione or 2,3‐bis[(1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy]naphthalene‐1,4‐dione, respectively. The advantages of these reactions are short reaction times, high‐to‐excellent reaction yields, operational simplicity, and mild experimental conditions. The new 1,2,3‐triazoles obtained were screened for their in vitro antibacterial activities and were subjected to molecular docking studies.     

Nickel(II) and copper(II) complexes of Schiff base ligands containing N4O2 and N4S2 donors with pyrrole terminal binding groups: Synthesis, characterization, X-ray structures, DFT and electrochemical studies

A series of hexadentate ligands, H₂L^m (m = 1−4), [1H-pyrrol-2-ylmethylene]{2-[2-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)ethoxy]phenyl}amine (H₂L¹), [1H-pyrrol-2-ylmethylene]{2-[4-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)butoxy]phenyl}amine (H₂L²), [1H-pyrrol-2-ylmethylene][2-({2-[(2-{[1H-pyrrol-2-ylmethylene]amino}phenyl)thio]ethyl}thio)phenyl]amine (H₂L³) and [1H-pyrrol-2-ylmethylene][2-({4-[(2-{[1H-pyrrol-2-lmethylene]amino}phenyl)thio]butyl}thio) phenyl]amine (H₂L⁴) were prepared by condensation reaction of pyrrol-2-carboxaldehyde with {2-[2-(2-aminophenoxy)ethoxy]phenyl}amine, {2-[4-(2-aminophenoxy)butoxy]phenyl}amine, [2-({2-[(2-aminophenyl)thio]ethyl}thio)phenyl]amine and [2-({4-[(2-aminophenyl)thio]butyl}thio)phenyl]amine respectively. Reaction of these ligands with nickel(II) and copper(II) acetate gave complexes of the form ML^m (m = 1−4), and the synthesized ligands and their complexes have been characterized by a variety of physico-chemical techniques. The solid and solution states investigations show that the complexes are neutral. The molecular structures of NiL³ and CuL², which have been determined by single crystal X-ray diffraction, indicate that the NiL³ complex has a distorted octahedral coordination environment around the metal while the CuL² complex has a seesaw coordination geometry. DFT calculations were used to analyse the electronic structure and simulation of the electronic absorption spectrum of the CuL² complex using TDDFT gives results that are consistent with the measured spectroscopic behavior of the complex. Cyclic voltammetry indicates that all copper complexes are electrochemically inactive but the nickel complexes with softer thioethers are more easily oxidized than their oxygen analogs.     

Toxicity of Thiophenes from Echinops transiliensis (Asteraceae) against Aedes aegypti (Diptera: Culicidae) Larvae

Structure? activity relationships of nine thiophenes, 2,2′: 5′,2″‐terthiophene ( 1 ), 2‐chloro‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐1‐yl acetate ( 2 ), 4‐(2,2′‐bithiophen‐5‐yl)but‐3‐yne‐1,2‐diyl diacetate ( 3 ), 4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yne‐1,2‐diyl diacetate ( 4 ), 4‐(2,2′‐bithiophen‐5‐yl)‐2‐hydroxybut‐3‐yn‐1‐yl acetate ( 5 ), 2‐hydroxy‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐1‐yl acetate ( 6 ), 1‐hydroxy‐4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yn‐2‐yl acetate ( 7 ), 4‐(2,2′‐bithiophen‐5‐yl)but‐3‐yne‐1,2‐diol ( 8 ), and 4‐[5‐(penta‐1,3‐diyn‐1‐yl)thiophen‐2‐yl]but‐3‐yne‐1,2‐diol ( 9 ), isolated from the roots of Echinops transiliensis, were studied as larvicides against Aedes aegypti. Structural differences among compounds 3, 5 , and 8 consisted in differing AcO and OH groups attached to C(3″) and C(4″), and resulted in variations in efficacy. Terthiophene 1 showed the highest activity (LC₅₀, 0.16 μg/ml) among compounds 1 – 9 , followed by bithiophene compounds 3 (LC₅₀, 4.22 μg/ml), 5 (LC₅₀, 7.45 μg/ml), and 8 (LC₅₀, 9.89 μg/ml), and monothiophene compounds 9 (LC₅₀, 12.45 μg/ml), 2 (LC₅₀, 14.71 μg/ml), 4 (LC₅₀, 17.95 μg/ml), 6 (LC₅₀, 18.55 μg/ml), and 7 (LC₅₀, 19.97 μg/ml). These data indicated that A. aegypti larvicidal activities of thiophenes increase with increasing number of thiophene rings, and the most important active site in the structure of thiophenes could be the tetrahydro‐thiophene moiety. In bithiophenes, 3, 5 , and 8 , A. aegypti larvicidal activity increased with increasing number of AcO groups attached to C(3″) or C(4″), indicating that AcO groups may play an important role in the larvicidal activity.     

Synthesis,Structure, DNA‐Binding Properties,and Cytotoxicity of Ruthenium(II) Polypyridyl Complexes

Many ruthenium(II) complexes show high antitumor activities, and the in vitro antitumor activities are usually related to DNA binding. We designed and synthesized two Ru^II polypyridyl complexes, [Ru(dmp)₂(fpp)]²⁺ (dmp=2,9‐dimethyl‐1,10‐phenanthroline; fpp=2‐[3,4‐(difluoromethylenedioxy)phenyl]imidazo[4,5‐f] [1,10]phenanthroline and [Ru(phen)₂(fpp)]²⁺ (phen=1,10‐phenanthroline). The DNA‐binding properties of these complexes have been investigated by spectroscopic titration, DNA melting experiments, viscosity measurements, and photoactivated cleavage. The mechanism studies of photocleavage revealed that singlet oxygen (¹O₂) and superoxide anion radical (O$\rm{{_{2}^{{^\cdot} -}}}$ ) may play an important role in the photocleavage. The cytotoxicity of complexes 1 and 2 have been evaluated by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide) method; complex 2 shows slightly higher anticancer potency than 1 does against all the cell lines screened.     

Design,Synthesis, Lipophilic Properties,and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors

We report the synthesis of compounds structurally related to the high‐affinity dopamine D₄ receptor ligand N‐{2‐[4‐(3‐cyanopyridin‐2‐yl)piperazin‐1‐yl]ethyl}‐3‐methoxybenzamide ( 1e ). All compounds were specifically designed as potential PET radioligands for brain D₄ receptor visualization, having lipophilicity within a range for brain uptake and weak non‐specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope ¹¹C or ¹⁸F. The best compound of the series, N‐{2‐[4‐(4‐chlorophenyl)piperazin‐1‐yl]ethyl}‐6‐fluoropyridine‐3‐carboxamide ( 7a ), displayed excellent selectivity over D₂ and D₃ receptors (>100‐fold), but its D₄ receptor affinity was suboptimal for imaging of brain D₄ receptors (K_i=30 nM ).     

Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives

Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and intramolecular cyclization reactions are suitable synthetic methods to generate chemically diverse diketopiperazine system, such as hexahydropyrrolo[1,2-a][1,3]thiazolo[3,2-d]pyrazine-5,10-dione (structure I), hexahydropyrrolo[1,2-a] [1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure II) and spiroindol-2-one[3,3′]hexahydro-5,10H-pyrrolo[1,2-a][1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure III). Some of these compounds, especially those who belong to the series I and II, showed interesting cytotoxic activity.