Synthesis and Biological Activity of 2-Benzo[b]thienyl and 2-Bithienyl Amidino-Substituted Benzothiazole and Benzimidazole Derivatives.

Novel benzo[b]thienyl- and 2,2'-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents.

Antibacterial and antiproliferative activity of novel 2-benzimidazolyl- and 2-benzothiazolyl-substituted benzo[b]thieno-2-carboxamides.

Novel nitro (3a-3f)- and amino (4a-4f and 5a-5f)-substituted 2-benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides were designed and synthesized as potential antibacterial agents. The antibacterial activity of these compounds has been evaluated against Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Moraxella catarrhalis). The most promising antibacterial activity was observed for the nitro- and amino-substituted benzimidazole derivatives 3a, 4a, 5a and 5b with MICs 2-8 [Formula: see text].

Synthesis, antitumor activity and DNA binding features of benzothiazolyl and benzimidazolyl substituted isoindolines.

In this paper novel isoindolines substituted with cyano and amidino benzimidazoles and benzothiazoles were synthesized as new potential anti-cancer agents. The new structures were evaluated for antiproliferative activity, cell cycle changes, cell death, as well as DNA binding and topoisomerase inhibition properties on selected compounds. Results showed that all tested compounds exerted antitumor activity, especially amidinobenzothiazole and amidinobenzimidazole substituted isoindolin-1-ones and benzimidazole substituted 1-iminoisoindoline that showed antiproliferative effect in the submicromolar range.

Synthesis and antiproliferative activity of amino-substituted benzimidazo[1,2-α]quinolines as mesylate salts designed by 3D-QSAR analysis.

An experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived on an available database of compounds with previously measured activities. Our QSAR analysis revealed that an increase of the antiproliferative activities towards H460, HCT 116, MCF-7 and SW 620 cells will be obtained if new compounds are charged at a pH range from 5 to 7 and if their hydrophobicity is increased compared to the dataset compounds.

Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties.

Within this manuscript design, synthesis of novel 2-imidazolinyl substituted benzo[b]thieno-2-carboxamides bearing either benzimidazole or benzothiazole subunit and biological activity are presented and described. The antiproliferative activities were assessed in vitro on a panel of human cancer cell lines. Tested compounds showed moderate activity while cytotoxicity on normal fibroblasts was lower in comparison with 5-fluorouracile.

Antioxidative and antiproliferative activities of novel pyrido[1,2-a]benzimidazoles.

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines-cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure-activity relationships among the synthesized compounds are discussed.

Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties.

We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity.

Novel 2-Thienyl- and 2-Benzothienyl-Substituted 6-(2-Imidazolinyl)Benzothiazoles: Synthesis; in vitro Evaluation of Antitumor Effects and Assessment of Mitochondrial Toxicity.

Background: Differently substituted thiophenes are largely studied due to their diverse pharmacological properties, especially anticancer activity. Recent studies have reported on interesting benzothiophene compounds antitumor properties and we also recently reported on the synthesis, strong antitumor activities and DNA binding features of substituted thieno[3',2':4,5]thieno- and benzo[b]thieno[2,3-c]quinolones, containing different substituents, mostly amidino- or substituted amidino- groups.

Objective: The objective of presented paper was to prepare a series of novel cationic 2-thiophene and 2- benzothiophene substituted 6-(2- imidazolinyl)benzothiazole derivatives and to test their antiproliferative activity against several human cancer cell lines.

Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2-a]quinoline derivatives tested in 2D and 3D cell culture systems.

Due to a poor clinical predictive power of 2D cell cultures, standard tool for in vitro assays in drug discovery process, there is increasing interest in developing 3D in vitro cell cultures, biologically relevant assay feasible for the development of robust preclinical anti-cancer drug screening platforms. Herein, we tested amidino-substituted benzimidazoles and benzimidazo[1,2-a]quinolines as a small platform for comparison of antitumor activity in 2D and 3D cell culture systems and correlation with structure-activity relationship. 3D cell culture method was applied on a human cancer breast (SK-BR-3, MDA-MB-231, T-47D) and pancreatic cancer cells (MIA PaCa-2, PANC-1).

Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors.

The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site.

Novel phenyl and pyridyl substituted derivatives of isoindolines: Synthesis, antitumor activity and DNA binding features.

Novel phenyl-substituted (3a-3d, 4a, 5, 8a, 8b and 9a) and pyridyl-substituted (3e-3i, 4b, 8c-8e, 9b and 9c) isoindolines were prepared in the reaction of o-phthalaldehyde and corresponding substituted aromatic and heteroaromatic amines by modification of reaction conditions from low to high temperature and from neutral to acidic environment. The antiproliferative activity of chosen substituted isoindolines was assessed on a panel of tumour cell lines and normal human fibroblasts. The majority of tested compounds was active at the highest tested concentrations phenyl-substituted isoindolines 3a and 3b and pyridyl-substituted isoindoline 3g showed a selective effect at micromolar concentrations on HepG2 cell line in comparison with other tested tumour cell lines and normal human fibroblasts.

Synthesis, antiproliferative activity and DNA binding properties of novel 5-aminobenzimidazo[1,2-a]quinoline-6-carbonitriles.

The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets.

Anilides and quinolones with nitrogen-bearing substituents from benzothiophene and thienothiophene series: synthesis, photochemical synthesis, cytostatic evaluation, 3D-derived QSAR analysis and DNA-binding properties.

A series of new anilides (2a-c, 4-7, 17a-c, 18) and quinolones (3a-b, 8a-b, 9a-b, 10-15, 19) with nitrogen-bearing substituents from benzo[b]thiophene and thieno[2,3-c]thiophene series are prepared. Benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones (3a-b, 8a-b) are synthesized by the reaction of photochemical dehydrohalogenation from corresponding anilides. Anilides and quinolones were tested for the antiproliferative activity.

New anticancer active and selective phenylene-bisbenzothiazoles: synthesis, antiproliferative evaluation and DNA binding.

Novel amidino-derivatives of phenylene-bisbenzothiazoles were synthesized and tested for their antiproliferative activity against several human cancer cell lines, as well as DNA-binding properties. The synthetic approach used for preparation of isomeric amidino substituted-phenylene-bis-benzothyazoles 3a-3f was achieved by condensation reaction of isophthaloyl dichloride 1a and terephthaloyl dichloride 1b or with phthalic acid 1c with 5-amidinium-2-aminobenzothiolate 2a and 5-(imidazolinium-2-yl)-2-aminobenzothiolate 2b in good yields. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid.

Antiproliferative potency of novel benzofuran-2-carboxamides on tumour cell lines: cell death mechanisms and determination of crystal structure.

In this manuscript the synthesis and biological activity of novel heterocyclic derivatives of benzofuran-2-carboxamides 3a-j and 6a-f is presented. Biological evaluation in vitro revealed that only few compounds exerted concentration-depended antiproliferative effects on tumour cell lines at micromolar concentrations. In particular, 2-imidazolynyl substituted compound 6f showed selectivity on SK-BR-3 cell line while 2-N-acetamidopyridyl substituted 3h and 2-imidazolynyl substituted amide 3i showed selective concentration-dependent antiproliferative effects on SW620 cell line.

Synthesis and antiproliferative evaluation of some new amidino-substituted bis-benzothiazolyl-pyridines and pyrazine.

Novel diamidino substituted conformationally restricted derivatives of bis-benzothiazolyl-pyridines and pyrazine were synthesized and their antiproliferative activity against several human cancer cell lines were determinated. The synthetic approach used for preparation of isomeric amidinobenzotiazolyl disubstituted pyridines 3a-3k and pyrazine 3l was achieved by condenzation reaction of commercially available pyridine and pyrazine dicarboxylic acids with amidino- 2a and 2-imidazolinyl-substituted 2-aminothiophenol 2b in polyphosphoric acid in moderate to good yield. The condenzation reaction was greatly optimized.

Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis.

A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity.

Novel biologically active nitro and amino substituted benzimidazo[1,2-a]quinolines.

This manuscript described the synthesis and biological activity of novel nitro substituted E-2-styryl-benzimidazoles and E-2-(2-benzimidazolyl)-3-phenylacrylonitriles and nitro and amino substituted benzimidazo[1,2-a]quinolines (4-5, 6-11, 17-20, and 21-32). All of the compounds showed significant growth inhibitory effect towards five tumor cell lines, whereby the IC(50) concentrations of 11, 20, 28, 29, 30, 32 are in the low micromolar range (IC(50)=2-19 μM). The DNA binding experiments did not show significant affinity of two selected compounds towards ct-DNA.

Novel pentamidine derivatives: synthesis, anti-tumor properties and polynucleotide-binding activities.

Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series.

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies.

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity.

Synthesis, spectroscopic characterization and antiproliferative evaluation in vitro of novel Schiff bases related to benzimidazoles.

A series of novel benzimidazole substituted Schiff bases were synthesized by reaction of aromatic aldehydes with corresponding 2-aminobenzimidazoles. Their structure has been studied by 1H and 13C NMR, IR and UV/Vis spectroscopy. Majority of prepared Schiff bases were tested on their antiproliferative activity in vitro and exerted non-specific antiproliferative activity on the tested cell lines at the highest tested concentration.

Putative mechanisms of antitumor activity of cyano-substituted heteroaryles in HeLa cells.

Six recently synthesized cyano-substituted heteroaryles, which do not bind to DNA but are highly cytotoxic against the human tumor cell line HeLa, were analyzed for their antitumor mechanisms of action (MOA). They did not interfere with the expression of human papillomavirus oncogenes integrated in the HeLa cell genome, but they did induce strong G1 arrest and result in the activation of caspase-3 and apoptosis. A computational analysis was performed that compared the antiproliferative activities of our compounds in 13 different tumor cell lines with those of compounds listed in the National Cancer Institute database.

Benzimidazole derivatives related to 2,3-acrylonitriles, benzimidazo[1,2-a]quinolines and fluorenes: synthesis, antitumor evaluation in vitro and crystal structure determination.

A synthesis and biological evaluation of new benzimidazole derivatives, related to 2,3-disubstituted acrylonitriles, benzimidazo[1,2-a]quinoline-6-carbonitriles and heteroaromatic fluorenes was described. The molecular and crystal structures of three compounds 4, 16 and 17 reveal that non-fused fluoro derivative, 4, deviates from planarity by 13.11(2) degrees, while fused methyl, 16, and fluoro, 17, derivatives are planar within 4 degrees exhibiting a planar aromatic surface capable to intercalate into double-stranded DNA.

Novel diamidino-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes: synthesis, antiproliferative and DNA binding properties.

A series of new diamidino-, diisopropylamidino-, and diimidazolinyl-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes were successfully prepared and evaluated for their antiproliferative activity on tumor cell lines in vitro, DNA binding propensity, and sequence selectivity as well as cellular distribution. A strong antiproliferative effect of the tested compounds was observed on all tested cell lines in a concentration-dependent response pattern. In general, imidazolinyl-substituted derivatives and/or the thiophene core were in correlation with increased antiproliferative activity.