Umbelliferone and Its Synthetic Derivatives as Suitable Molecules for the Development of Agents with Biological Activities: A Review of Their Pharmacological and Therapeutic Potential.

Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer therapy. Also, its derivatives are endowed with great potential for therapeutic applications due to their broad spectrum of biological activities such as anti-inflammatory, antioxidant, neuroprotective, antipsychotic, antiepileptic, antidiabetic, antimicrobial, antiviral, and antiproliferative effects. Moreover, 7-hydroxycoumarin ligands have been implemented to develop 7-hydroxycoumarin-based metal complexes with improved pharmacological activity. Besides therapeutic applications, umbelliferone analogues have been designed as fluorescent probes for the detection of biologically important species, such as enzymes, lysosomes, and endosomes, or for monitoring cell processes and protein functions as well various diseases caused by an excess of hydrogen peroxide. Furthermore, 7-hydroxy-based chemosensors may serve as a highly selective tool for Al3+ and Hg2+ detection in biological systems. This review is devoted to a summary of the research on umbelliferone and its synthetic derivatives in terms of biological and pharmaceutical properties, especially those reported in the literature during the period of 2017-2023. Future potential applications of umbelliferone and its synthetic derivatives are presented.

Indole-Acrylonitrile Derivatives as Potential Antitumor and Antimicrobial Agents-Synthesis, In Vitro and In Silico Studies.

A series of 2-(1H-indol-2-yl)-3-acrylonitrile derivatives, 2a-x, 3, 4a-b, 5a-d, 6a-b, and 7, were synthesized as potential antitumor and antimicrobial agents. The structures of the prepared compounds were evaluated based on elemental analysis, IR, 1H- and 13NMR, as well as MS spectra. X-ray crystal analysis of the representative 2-(1H-indol-2-yl)-3-acrylonitrile 2l showed that the acrylonitrile double bond was Z-configured. All compounds were screened at the National Cancer Institute (USA) for their activities against a panel of approximately 60 human tumor cell lines and the relationship between structure and in vitro antitumor activity is discussed. Compounds of interest 2l and 5a-d showed significant growth inhibition potency against various tumor cell lines with the mean midpoint GI50 values of all tests in the range of 0.38-7.91 µM. The prominent compound with remarkable activity (GI50 = 0.0244-5.06 µM) and high potency (TGI = 0.0866-0.938 µM) against some cell lines of leukemia (HL-60(TB)), non-small cell lung cancer (NCI-H522), colon cancer (COLO 205), CNS cancer (SF-539, SNB-75), ovarian cancer ((OVCAR-3), renal cancer (A498, RXF 393), and breast cancer (MDA-MB-468) was 3-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-indol-2-yl)acrylonitrile (5c). Moreover, the selected 2-(1H-indol-2-yl)-3-acrylonitriles 2a-c and 2e-x were evaluated for their antibacterial and antifungal activities against Gram-positive and Gram-negative pathogens as well as Candida albicans. Among them, 2-(1H-indol-2-yl)-3-(1H-pyrrol-2-yl)acrylonitrile (2x) showed the most potent antimicrobial activity and therefore it can be considered as a lead structure for further development of antimicrobial agents. Finally, molecular docking studies as well as drug-likeness and ADME profile prediction were carried out.

Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential.

Four copper(II) complexes, C1-4, derived from 1-(isoquinolin-3-yl)heteroalkyl-2-one ligands L1-4 were synthesized and characterized using an elemental analysis, IR spectroscopic data as well as single crystal X-ray diffraction data for complex C1. The stability of complexes C1-4 under conditions mimicking the physiological environment was estimated using UV-Vis spectrophotometry. The antiproliferative activity of both ligands L1-4 and copper(II) compounds C1-4 were evaluated using an MTT assay on four human cancer cell lines, A375 (melanoma), HepG2 (hepatoma), LS-180 (colon cancer) and T98G (glioblastoma), and a non-cancerous cell line, CCD-1059Sk (human normal skin fibroblasts). Complexes C1-4 showed greater potency against HepG2, LS180 and T98G cancer cell lines than etoposide (IC50 = 5.04-14.89 µg/mL vs. IC50 = 43.21->100 µg/mL), while free ligands L1-4 remained inactive in all cell lines. The prominent copper(II) compound C2 appeared to be more selective towards cancer cells compared with normal cells than compounds C1, C3 and C4. The treatment of HepG2 and T98G cells with complex C2 resulted in sub-G1 and G2/M cell cycle arrest, respectively, which was accompanied by DNA degradation. Moreover, the non-cytotoxic doses of C2 synergistically enhanced the cytotoxic effects of chemotherapeutic drugs, including etoposide, 5-fluorouracil and temozolomide, in HepG2 and T98G cells. The antimicrobial activities of ligands L2-4 and their copper(II) complexes C2-4 were evaluated using different types of Gram-positive bacteria, Gram-negative bacteria and yeast species. No correlation was found between the results of the antiproliferative and antimicrobial experiments. The antioxidant activities of all compounds were determined using the DPPH and ABTS radical scavenging methods. Antiradical tests revealed that among the investigated compounds, copper(II) complex C4 possessed the strongest antioxidant properties. Finally, the ADME technique was used to determine the physicochemical and drug-likeness properties of the obtained complexes.

Synthesis, Structure and Cytotoxic Properties of Copper(II) Complexes of 2-Iminocoumarins Bearing a 1,3,5-Triazine or Benzoxazole/Benzothiazole Moiety.

A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC50 values ranging from 0.04 µM to 15.66 µM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7' of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7' of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.

A Mini-Review: Recent Advances in Coumarin-Metal Complexes With Biological Properties.

The coumarin nucleus is a recurring motif in both natural and synthetic compounds that exhibit a broad spectrum of biological properties including anticoagulant, anti-inflammatory, antioxidant, antiviral, antimicrobial and anticancer agents as well as enzyme inhibitors. On the other hand, it has been reported that the incorporation of a metal ion into coumarin derivatives can increase the activity of such complexes compared to coumarin-based ligands. Accordingly, some of them have been found to display promising antioxidant, antitumor or antibacterial activities. This mini-review briefly summarizes the recent development of coumarin-metal complexes with proven biological properties. The attention is also paid to agents for which practical applications in the detection of biologically important species may be found.

Synthesis, Structure and Cytotoxicity Testing of Novel 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives.

The appropriate 1-arylhydrazinecarbonitriles 1a-c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a-c, which are subsequently converted into the corresponding amides 4a-e, 8a-c, sulfonamides 5a-n, 9, ureas 6a-I, and thioureas 7a-d. The structures of the newly prepared derivatives 3a-c, 4a-e, 5a-n, 6a-i, 7a-d, 8a-c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1'-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC50 values in the range of 2.38-3.77 µM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.

Synthesis and Fluorescent Properties of Novel Isoquinoline Derivatives.

Isoquinoline derivatives have attracted great interest for their wide biological and fluorescent properties. In the current study, we focused on the synthesis of a series of novel isoquinoline derivatives substituted at position 3 of the heteroaromatic ring. Compounds were obtained in a Goldberg-Ullmann-type coupling reaction with appropriate amides in the presence of copper(I) iodide, N,N-dimethylethylenediamine (DMEDA), and potassium carbonate. The structures of novel isoquinolines were confirmed by IR, NMR, and elemental analysis, as well as X-ray crystallography. In the course of our research work, the visible fluorescence of this class of compounds was observed. The above findings prompted us to investigate the optical properties of the selected compounds.

Synthesis, Structure, Chemical Stability, and In Vitro Cytotoxic Properties of Novel Quinoline-3-Carbaldehyde Hydrazones Bearing a 1,2,4-Triazole or Benzotriazole Moiety.

A small library of novel quinoline-3-carbaldehyde hydrazones (Series 1), acylhydrazones (Series 2), and arylsulfonylhydrazones (Series 3) bearing either a 1,2,4-triazole or benzotriazole ring at position 2 was prepared, characterized by elemental analyses and IR, NMR, and MS spectra, and then subjected to in vitro cytotoxicity studies on three human tumor cell lines: DAN-G, LCLC-103H, and SISO. In general, compounds 4, 6, and 8 substituted with a 1,2,4-triazole ring proved to be inactive, whereas the benzotriazole-containing quinolines 5, 7, and 9 elicited pronounced cancer cell growth inhibitory effects with IC50 values in the range of 1.23⁻7.39 µM. The most potent 2-(1H-benzotriazol-1-yl)-3-[2-(pyridin-2-yl)hydrazonomethyl]quinoline (5e) showed a cytostatic effect on the cancer cell lines, whereas N'-[(2-(1H-benzotriazol-1-yl)quinolin-3-yl)methylene]-benzohydrazide (7a) and N'-[(2-1H-benzotriazol-1-yl)quinolin-3-yl)methylene]-naphthalene-2-sulfonohydrazide (9h) exhibited selective activity against the pancreas cancer DAN-G and cervical cancer SISO cell lines. Based on the determined IC50 values, the compound 5e seems to be leading compound for further development as anticancer agent.

Are Alpha-2D Adrenoceptor Subtypes Involved in Rat Mydriasis Evoked by New Imidazoline Derivatives: Marsanidine and 7-Methylmarsanidine?

The imidazoline compounds may produce mydriasis after systemic administration to some species (rats, cats, and mice). In mydriatic activity of imidazolines, α2D-adrenoceptors subtype(s) seems to be involved. In this study, the pupil dilatory effect evoked by 2 newly synthesized imidazoline derivatives-α2-adrenoceptor agonists: marsanidine and 7-methylmarsanidine-was compared. The compounds were tested alone as well as in the presence of α2-adrenoceptor antagonists (nonselective, yohimbine, and selective toward the following α2-adrenoceptor subtypes-α2A-2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408), α2B-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239), α2C-JP1302, α2D-2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole hydrochloride [RX821002]). The agonists were studied in male Wistar rats and were administered intravenously in cumulative doses. The antagonistic compounds were given in a single dose before the experiment with marsanidine or 7-methylmarsanidine. Pupil diameter was measured with stereoscopic microscope equipped in green light filter. Marsanidine and 7-methylmarsanidine exerted marked mydriatic effects. BRL44408, JP1302, and ARC239 did not cause significant parallel shift to the right of the dose-effect curves obtained for both imidazolines. In case of yohimbine and RX821002, the marked parallel shifts of dose-response curves were observed, with the antagonistic effects of RX821002 more pronounced. In vivo pharmacodynamics experiment suggests that α2D-adrenoceptor subtype is mainly engaged in mydriatic effects evoked in rats by imidazoline derivatives, in particular by clonidine.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED50 in µmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logkw, were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED50) and logkw values was obtained. The lack of "predictive" QSAR for the whole series of the structurally diverse agents is probably due to a complex mechanism of the ligand-alpha2-adrenergic receptor interactions, which are predominantly of a highly structurally specific polar nature. Such interactions are difficult to quantify with the established chemical structural descriptors, contrary to the less specific, molecular bulkiness-related interactions.

Synthesis and Preliminary Cytotoxicity Studies of 1-[1-(4,5-Dihydrooxazol- 2-yl)-1H-indazol-3-yl]-3-phenylurea and 3-phenylthiourea Derivatives.

BACKGROUND: N-substituted 3-amino-1H-indazoles represent an interesting class of biologically active compounds. Among them, derivatives containing phenylurea moiety are of particular interest. Such compounds have been found to possess inhibitory activity against cancer cell growth. Additionally, various oxazoline-containing compounds have also been designed as potential anticancer agents. OBJECTIVE: The aim of this work was to obtain a new class of N-substituted 3-amino-1H-indazole derivatives with cytotoxic activity towards cancer cells. METHOD: Two series of 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylurea and 3- phenylthiourea derivatives 7-17 and 18-22, respectively, were prepared and screened for their potential in vitro cytotoxic activities against lung carcinoma LCLC-103H cell line using a crystal violet microtiter plate assay. RESULTS: All the urea derivatives, except the compound 8, were inactive at a concentration of 20 µM attainable in cancer cells, while the thiourea derivatives showed a pronounced cancer cell growth inhibitory effects. The most potent 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-ptolylthiourea (19) exhibited cytotoxicity on the lung cancer LCLC-103H and cervical cancer SISO cell lines at a concentration of 10 µM. Moreover, compound 19 displayed cytostatic activity against pancreas cancer DAN-G cell line. CONCLUSION: The 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylthiourea derivatives described herein may serve as a useful scaffold for the search for novel anticancer agents.

COMPARISON OF THE EFFECTS OF MARSANIDINE DERIVATIVES ON RAT CARDIOVASCULAR SYSTEM.

Since clonidine was introduced in clinical practice, attempts are still made to obtain substances capable of centrally controlling blood pressure, however with pharmacological profile better than currently avail- able, such as moxonidine and rilmenidine. Recently synthesized indazole derivatives exert promising action on blood pressure and heart rate in Wistar rats. In the present study, our aim was to check which of tested substituted compound exerts the best effect on basic circulatory parameters. Effects of marsanidine (M), 7-Me- marsanidine (7-Me-M), 7-Cl-marsanidine (7-Cl-M) and 7-F-marsanidine (7-F-M) on blood pressure, heart rate and diuresis were compared. Male Wistar rats were receiving iv. tested compounds in two doses: 10 or 100 pg/kg b.w. Mean arterial pressure (MAP), heart rate (HR) and ECG were recorded continuously. Urine samples were collected before and after administration of tested imidazolines. Obtained data were filtered and subjected to statistical analysis. All tested compounds caused a profound decrease of MAP. 7-M-M reduced blood pressure to the highest extent when used in 10 µg/kg b.w. dose. 7-F-M in dose of 100 µg/kg b.w. caused the strongest drop of MAP. The weakest and the shortest effect in duration was observed after M administration. HR was reduced after administration of each compound while the strongest effect was observed after 7-M-M administration in dose of 10 µg/kg b.w. and after 7-Cl-M administered in dose of 100 µg/kg b.w. Again, the weakest and the shortest in duration effect was observed after M administration. The highest increase of diuresis was observed after 7-M-M administration. These data suggest that methyl substituent in 7 position of indazole ring is the most effective in improving hypotensive effects of newly synthesized imidazolidine derivatives.

1-[(Imidazolidin-2-yl)imino]-1H-indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies.

A series of 1-[(imidazolidin-2-yl)imino]-1H-indole analogues of hypotensive α2 -AR agonists, 1-[(imidazolidin-2-yl)imino]-1H-indazoles, was synthesized and tested in vitro for their activities at α1 - and α2 -adrenoceptors as well as imidazoline I1 and I2 receptors. The most active 1-[(imidazolidin-2-yl)imino]-1H-indoles displayed high or moderate affinities for α1 - and α2 -adrenoceptors and substantial selectivity for α2 -adrenoceptors over imidazoline-I1 binding sites. The in vivo cardiovascular properties of indole derivatives 3 revealed that substitution at C-7 position of the indole ring may result in compounds with high cardiovascular activity. Among them, 7-fluoro congener 3g showed the most pronounced hypotensive and bradycardic activities in this experiment at a dose as low as 10 µg/kg i.v. Metabolic stability of the selected compounds of type 3 was determined using both in vitro and in silico approaches. The results indicated that these compounds are not vulnerable to rapid first-phase oxidative metabolism.

Imidazoline scaffold in medicinal chemistry: a patent review (2012-2015).

INTRODUCTION: Until very recently, the 'imidazoline drugs' were perceived as a class of central and/or peripheral sympatholytics and vasodilators acting at either the imidazoline binding sites and/or α-adrenergic receptors. However, in recent years it has become evident that the imidazoline scaffold is also contained in synthetic agents that exhibit a broad spectrum of biological activities. AREAS COVERED: This review provides an insight into the patents filed in the years 2012-2015, and considers 2-imidazoline-containing compounds with proven biological properties. Special attention is paid to agents for which practical applications as active ingredients of pharmaceutical compositions, diagnostic imaging agents, insecticides and herbicides, may be found. EXPERT OPINION: 2-Substituted imidazolines can exist in multiple tautomeric forms. The implication is that imidazolines and their imidazolidine tautomers cannot be regarded as isofunctional structures and the term 'imidazoline scaffold' should be treated with caution. Nevertheless, for medicinal chemists the progress made in development of both the imidazoline- and imidazolidine-containing agents useful for the treatment of neurodegenerative, inflammatory, autoimmune, cancer, and infectious diseases is of the utmost importance.

Circulatory effect of TCS-80, a new imidazoline compound, in rats.

BACKGROUND: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. METHODS: Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. RESULTS: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. CONCLUSION: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.

Vagotomy reveals the importance of the imidazoline receptors in the cardiovascular effects of marsanidine and 7-ME-marsanidine in rats.

BACKGROUND: The recently synthesized novel benzazole derivates - marsanidine (1-[(imidazolidin-2-yl)imino]indazole) and 7-Me-marsanidine (1-[(imidazolidin-2-yl)imino]-7-methylindazole) display promising effects on the circulatory system. We previously indicated that i.v. administration of both compounds decreased the mean arterial blood pressure (MAP) and heart rate (HR) in rats. The cardiovascular effect of the tested compounds may consist not only in inhibiting the sympathetic, but also in activating the parasympathetic pathways related to vagal nerves. Present experiments were performed to determine how vagotomy, with or without an α2 adrenoreceptor blockade, may affect hypotensive and HR limiting actions of marsanidine and 7-Me-marsanidine. METHODS: Both compounds were infused i.v. (10 µg/kg b.w.) to anesthetized rats, half of which underwent vagotomy. Half the intact, and half the vagotomised rats received RX821002, an α2 adrenorereceptor inhibitor. MAP and HR were monitored directly throughout the experiment. RESULTS: Vagotomy enhanced hypotension observed after marsanidine administration. The α2 adrenergic blockade abolished the action of marsanidine in both the intact and vagotomised rats. Vagotomy did not affect the 7-Me-marsanidine-induced decrease of MAP or HR. However, it abolished the reducing effect of the α2 adrenergic receptor blockade on the hypotension triggered by 7-Me-marsanidine. CONCLUSION: The results show that although cardiovascular effects of marsanidine and 7-Me-marsanidine are not mediated by the vagal nerves, vagotomy enhanced sensitivity of the sympathetic pathways for the tested compounds. While the action of marsanidine in vagotomised and intact rats may be explained by activation of the α2 adrenoreceptors, the effects of 7-Me-marsanidine seem to be α2 adrenoreceptor-independent. It seems likely that activation of I1 imidazoline receptors could mediate the observed effects.

Marsanidine and 7-Me-marsanidine, the new hypotensive imidazolines augment sodium and urine excretion in rats.

BACKGROUND: We have recently described the synthesis and circulatory properties of two novel centrally acting imidazoline agents: marsanidine (1-[(imidazolidin-2-yl)imino]indazole) and 7-Me-marsanidine (1-[(imidazolidin-2-yl)imino]-7-methylindazole). Marsanidine has proven to be a highly selective α2-adrenoceptor ligand with the α2/I1 selectivity ratio of 3879, while 7-Me-marsanidine has been shown to be a mixed a2-adrenoceptor/imidazoline I1 receptor agonist with the a2/I1 selectivity ratio of 7.2. In the same paper, we indicated that iv administration of both compounds to Wistar rats induced a decrease in blood pressure and heart rate. The hypotensive effect of the iv administered imidazolines might be mediated not only through activation of the central α2 and/or I1 receptors but also through subsequent decrease of the renal sympathetic nerve activity and a direct effect on peripheral receptors. The present studies were performed to determine whether the newly synthesized compounds might influence the diuresis and sodium excretion in rats. METHODS: Both compounds were infused iv to anesthetized rats in the dose of 100 µg/kg b.w. The diuresis and sodium concentration in urine and blood samples were determined. The mean arterial blood pressure and heart rate were monitored directly throughout the experiment. RESULTS: A significant increase of diuresis and natriuresis was observed within 40 min after the administration of both marsanidine and 7-Me-marsanidine, in comparison to both the control period and the control group. However, between the 20 and 40 min of the experiment the natriuretic and diuretic effect of 7-Me-marsanidine was markedly higher than that of marsanidine. CONCLUSION: Our study indicates that the new hypotensive imidazoline compounds of marsanidine and 7-Me-marsanidine increase diuresis and natriuresis in rats. However, the effect of 7-Me-marsanidine is markedly more potent, probably due to its moderate affinity to the I1-imidazoline receptor.

Synthesis, cytotoxicity testing, and structure-activity relationships of novel 6-chloro-7-(4-phenylimino-4H-3,1-benzoxazin-2-yl)-3-(substituted)-1,4,2-benzodithiazine 1,1-dioxides.

A new series of 16 6-chloro-1,1-dioxo-7-{4-[(4-R(1)-phenyl)imino]-4H-3,1-benzoxazin-2-yl}-3-(substituted amino)-1,4,2-benzodithiazines 7-22 was prepared in order to evaluate the cytotoxic activity against six human cancer cell lines. The structures of the new compounds were confirmed by IR, (1)H-, and (13)C-NMR, elemental analysis and in the cases of 11 and 31 by X-ray crystal structure analysis. This analysis showed that contrary to our earlier report the structures contain a benzoxazine ring instead of the proposed quinazolinone ring. The bioassay indicated that the benzodithiazine derivatives 7-22 possess cancer cell growth-inhibitory properties. Some compounds showed a high level of selectivity for certain cell lines. The most active compounds 11, 12, 16, 19, 21, and 22 exhibited potency higher or comparable to cisplatin. The compounds were particularly effective in LCLC-103H and MCF-7 cell lines with IC(50) values of 0.49-1.60 µM. Quantitative structure activity relationships (QSAR) revealed that a chloro substituent R(1) in the phenyl ring as well as the shape of the substituted amino group at R(2) (e.g., unsaturation is beneficial) are important for potency.

3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor.

A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective α(2)-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display α(2)-adrenoceptor affinity at nanomolar concentrations (K(i)=39.4, 15.9 and 22.6nM, respectively) and relatively high α(2)/I(1) selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at α(2A)-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01mg/kg iv.

Synthesis and biological activity of some 2-imidazolinylhydrazone derivatives.

A series of N-(imidazolidin-2-ylidene)hydrazones and N-(4,5-dihydro-1H-imidazol-2-yl)-N-methylhydrazones were prepared and examined for alpha 1-, alpha 2-adrenergic and imidazoline I1, I2 receptors binding affinities as well as cytotoxic activity against human tumor cell lines. Among the compounds tested, 2-naphthaldehyde N-(imidazolidin-2-ylidene)hydrazone (3e) exhibited a significant affinity for both alpha 2-adrenergic and imidazoline I1 receptors (Ki = 94.3 nM and IC50 = 51.7 nM, respectively). Moreover, pyridine-2-carboxaldehyde N-(imidazolidin-2-ylidene)hydrazone (3l) showed the highest binding affinity to alpha 1-adrenoceptors (Ki = 24.6 nM), while quinoline-2-carboxaldehyde N-(imidazolidin-2-ylidene)hydrazone (3m) displayed the highest I2 affinity with a Ki value of 26.7 nM and a high selectivity with respect to alpha 2-adrenergic and imidazoline I1 receptors (Ki = 22470.0 nM and IC50 = 6145.0 nM, respectively). None of the tested N-(4,5-dihydro-1H-imidazol-2-yl)-N-methylhydrazones 4p-u displayed cytotoxic activity.