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The bicyclic ring system of indole (benzo[b]pyrrole) is a structural element of many therapeutic agents used in medical practice with diverse biological activities, including anticancer, antibacterial, antiviral, anti-inflammatory, analgesic, antipyretic and hypotensive drugs as well as antidepressants or antipsychotics. Indole compounds, both natural and synthetic, have long been used as anticancer drugs in the treatment of neoplastic diseases such as lung cancer, breast cancer, sarcomas, lymphomas, and tumors of the central nervous system. On the other hand, as antiemetic drugs, they are used in oncological patients undergoing chemotherapy and radiotherapy. Indole compounds regulate the functioning of the endocrine system and are used in the treatment of hyperprolactinemia, endometriosis, and central premature children’s puberty. They are important for the proper functioning of the nervous system and therefore are used in patients suffering from neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease. The indole ring is also the basis of drugs used, among others, in cardiovascular diseases - in the treatment of arterial hypertension, in the digestive system - in irritable bowel syndrome, in the respiratory system in particular in the case of asthma as well as in bone tissue diseases indicated for the treatment of osteoporosis. Indole derivatives are in the focus of many research centers, in which their new properties are constantly being discovered. It should be emphasized, that aromatic or heteroaromatic rings constituting the structural motif of compounds with different pharmacological effects are referred to as privileged structures. This group of heterocyclic compounds also includes indole. This article is intended to provide a review of currently used drugs containing the heterocyclic indole system in their structures and their possible clinical applications. The current directions of searching for novel indole-based drugs are also presented.

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.

The guanidine derivative 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)amino](phenylamino)methylene}benzamide (3) has been obtained by the reaction of one measure of 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]carbamothioyl}benzamide (2) with one measure of aniline in the presence of mercury(II) chloride and triethylamine in anhydrous dimethylformamide. The structure of product 3 was confirmed by 1H and 13C-NMR, infrared spectroscopy, and elemental analysis.

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 were determined using both in vitro and in silico approaches. The results indicated that these compounds are not vulnerable to rapid first phase oxidative metabolism. This article is protected by copyright. All rights reserved.

Background Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1 H -indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -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-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I 1 -imidazoline receptors and the lowest α 2 /I 1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α 2 -adrenergic and I 1 -imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α 2 -adrenergic and/or I 1 -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 α 2 -adrenoceptor antagonist, RX821002, or nonselective α 2 -adrenergic/I 1 -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 α 2 -adrenergic and I 1 -imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I 1 -imidazoline receptors than by the α 2 -adrenergic ones.

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.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.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.

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.

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.

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 α 2 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 α 2 adrenorereceptor inhibitor. MAP and HR were monitored directly throughout the experiment. Results Vagotomy enhanced hypotension observed after marsanidine administration. The α 2 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 α 2 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 α 2 adrenoreceptors, the effects of 7-Me-marsanidine seem to be α 2 adrenoreceptor-independent. It seems likely that activation of I 1 imidazoline receptors could mediate the observed effects.

The reaction of 2-chloro-4,5-dihydroimidazole (5) with 2-aminobenzohydrazides 6a–e led to the formation of 2-amino-N′-(imidazolidin-2-ylidene)benzohydrazides as zwitterions 7a–e, which on treatment with carbon disulfide in the presence of triethylamine afforded 3-(imidazolidin-2-ylideneamino)-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 8a–e. Compounds 8a–d were further converted into the corresponding 3-(imidazolidin-2-ylideneamino)quinazoline-2,4(1H,3H)-diones 9a–d using hydrogen peroxide–sodium hydroxide solution. The structures of the compounds prepared were established by elemental analyses, IR and NMR spectra as well as X-ray crystallographic analyses of 7e and 9a.

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.

Arylsulfonyl isocyanates are commonly used for the production of arylsulfonyl carbamates and ureas, finding many commercial uses. Isocyanates are toxic and have usually been prepared using processes that require the handling of dangerous chemicals such as phosgene. Dimethylaminopyridinium carbamoylides (3a–d and 25) have been designed as new, safer and non-hazardous substitutes of arylsulfonyl isocyanates and the previously unreported benzimidazol-1-yl isocyanate.

A series of 2-mercapto-substituted-benzenesulfonamides has been prepared by a unique two-step procedure starting from the corresponding 2-chloro-substituted benzenesulfonamides. Compounds bearing an unsubstituted mercapto group and the corresponding S-benzoyl derivatives were investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), i.e., the cytosolic, ubiquitous isozymes CA I and II, as well as the transmembrane, tumor associated isozymes CA IX and XII. These derivatives were medium potency hCA I inhibitors (K(I)s in the range of 1.5-5.7 microM), two derivatives were strong hCA II inhibitors (K(I)s in the range of 15-16 nM), whereas the others showed weak activity. These compounds inhibited hCA IX with inhibition constants in the range 160-1950 nM and hCA XII with inhibition constants in the range 1.2-413 nM. Some of these derivatives showed a certain degree of selectivity for inhibition of the tumor-associated over the cytosolic isoforms, being thus interesting leads for the development of potentially novel applications in the management of hypoxic tumors which overexpress CA IX and XII.

The reaction of 2-chloro-4,5-dihydroimidazole (1) with aliphatic hydroxylamines 2−4 gives O-amidinylhydroxylamines 5−7 in contrast to the analogous reaction of 1 with N-arylhydroxylamines in which N-substitution occurs. A number of thiocarbamoylsulfenamides 8−10 have been prepared by the reaction of 5−7 with carbon disulfide under basic and mild conditions. The key step in the 1,5-OS amine migration involves the tandem nucleophilic addition-electrophilic amination reaction. The intermolecular version of this process using preformed triethylammonium dithiocarbamates gives the corresponding sulfenamides 14−16. Functionalized ethylenediamines 17−19 are obtained by treatment of 8 and 9 with amines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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 α 2 -adrenoceptor ligand with the α 2 /I 1 selectivity ratio of 3879, while 7-Me-marsanidine has been shown to be a mixed α 2 -adrenoceptor/imidazoline I1 receptor agonist with the α 2 /I 1 selectivity ratio of 7.2. In the same paper, we indicated that iv administration of both compounds toWistar 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 α 2 and/or I 1 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 Asignificant 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 I 1 -imidazoline receptor.

The title compounds are tested of their cytotoxic activity against 6 human cancer cell lines.

A new series of 16 6‐chloro‐1,1‐dioxo‐7‐{4‐[(4‐R1‐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, 1H‐, and 13C‐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 IC50 values of 0.49–1.60 µM. Quantitative structure activity relationships (QSAR) revealed that a chloro substituent R1 in the phenyl ring as well as the shape of the substituted amino group at R2 (e.g., unsaturation is beneficial) are important for potency., A new series of benzodithiazines was prepared and evaluated for their in‐vitro activity against six human cell lines. The most active compounds (R1=Cl, R2=aminomethylpyridine) exhibited potency higher than or comparable to cisplatin. WILEY‐VCH Verlag

The reactions of 6-chloro-3-methylthio-1,4,2-benzodithiazine 1,1-dioxide derivatives with appropriate diamines were investigated. Depending on the reaction conditions 2-mercaptobenzenesulfonamide derivatives or their oxidation product disulfides were obtained. All the compounds were tested at the US National Cancer Institute (Bethesda) for their in vitro anticancer and anti-HIV activities. The highest sensibility against leukemia cell lines was found for bis[2-(6-chloro-4-phenyl-3,4-dihydroquinazolin-2-yl)aminosulfonyl-5-chloro-4-(4-R 2 -phenylcarbamoyl)phenyl]disulfides (R 2 =H or Cl). The results of anti-HIV tests displayed moderate activity of N -(pirydo[3,2- d ]imidazol-2-yl)-2-mercaptobenzenesulfonamide.

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.

Novel benzazole derivatives bearing a (imidazolidin-2-yl)imino moiety at position 1 or 2 were synthesized by reacting 1-amino- or 2-aminobenzazoles with N, N'-bis( tert-butoxycarbonyl)imidazolidine-2-thione in the presence of HgCl 2. Structures of 1-[(imidazolidin-2-yl)imino]indazole (marsanidine, 13a) and free base of the 4-Cl derivative 12e were confirmed by X-ray single crystal structure analysis. Compound 13a was found to be the selective alpha 2-adrenoceptor ligand with alpha 2-adrenoceptor/imidazoline I 1 receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole ( 13k) proved to be a mixed alpha 2-adrenoceptor/imidazoline I 1 receptor agonist with alpha 2/I 1 selectivity ratio of 7.2. Compound 13k when administered intravenously to male Wistar rats induced a dose-dependent decrease in mean arterial blood pressure (ED50 = 0.6 microg/kg) and heart rate, which was attenuated following pretreatment with alpha 2A-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to alpha 2-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.

The reaction of 2-chloro-4,5-dihydroimidazole (1) with 2-aminoacetophenone hydrazones (2a-b) afforded 1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolines (3a-b) in contrast to the analogues reaction of 1 with 2-aminobenzophenone hydrazones (4a-e), which led to the formation of corresponding N -imidazolidin-2-ylidenehydrazones (5a-e). Compounds (5a-d) were further treated with carbon disulfide to give 5,10,11,12a -tetrahydro-6H,9H -imidazo[2', 1': 3,4][l,2,4]triazolo[l,5-c]quinazoline-6-thiones (6a-d). The structures of all new compounds obtained were established by elemental analyses and spectroscopic data (IR, NMR) as well as X-ray crystallographic analyses of 5a and 6a.

Reaction of 2-chloro-4,5-dihydroimidazole (1) with 2-aminobenzylamines (2a-d) afforded 2-[(imidazolidin-2-ylideneamino)methyl]-anilines (3a-d) which upon treatment with carbon disulfide gave 2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thiones (4a-d) and 3,4-dihydro-1H-quinazolin-2-thiones (5a-c). Analogous reaction of 1 with 2-aminobenzyl alcohol (6) led to the formation of [2-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]methanol hydrochloride (7) which was transformed into 1 -(4H-3,1-benzoxazin-2-yl)imidazolidin-2-thione (8).

Some 2-mercapto-substituted-benzenesulfonamides and their disulfides/sulfones were prepared and investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, CA I and II (cytosolic enzymes), and the tumor-associated CA IX and XII. Some mercaptans led to a consistent increase of inhibitory power (52.8- to 243-fold) over the corresponding oxidized (S-S type) derivatives, acting as potential hypoxia-activatable drugs.

Two enantiomers IR, 2S-(+)-cis (3a) and IS, 2R-(-)-cis (3b) of 1-[(4,5-dihydroimidazolidin-2-yl)imino]indan-2-ol were prepared by reacting 2-chloro-4,5-dihydroimidazole (1) with corresponding 1-amino-indan-2-ols (2a-b). The compounds obtained are structural analogues of PMS 952 agent containing imino bridge in place of methylene group. Compound 3a exhibited moderate almost equal activity at both imidazoline I2 receptors and alpha2-adrenoceptors, while enantiomer 3b was found to be selective for alpha2-adrenoceptors (alpha2/I2 selectivity ratio = 10.4).

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles have been identified as selective imidazoline I 2 /α 2 -adrenoceptor ligands. 4-Methyl ( 2 ) and 4-chloro ( 4 ) derivatives display I 2 affinity at nanomolar concentration ( K i = 4.4 and 17.7 nM, respectively) and high I 2 /α 2 selectivity ratio = 4226 and 5649, respectively. An evidence has been obtained that p K a value influences considerably the I 2 /α 2 -selectivity ratio of this class of imidazoline I 2 receptor ligands.

A series of variously substituted 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline derivatives 3-4 and 6-7 were prepared by the reactions of 2-chloro-4,3-dihydroimidazole (1) with the appropriate 2-aminophenyl ketones 2 and 5.The structures of the new compounds obtained were determined by elemental analysis as well as IR and NMR spectroscopic data. Biological activities of the compounds 3 and 6 was examined on P 2 membrane preparations obtained from rat whole brains and rat tail artery. Among the compounds tested, 5-methylidene-1,2,3,3-tetrahydroimidazo[2,1-b]quinazoline (6a) showed high and moderate binding affinities to I 2 imidazoline (K i = 5.2 nM) and α 2 -adrenergic (K i = 149 nM) receptors, respectively.

The reactions of 6-chloro-3-methylthio-1,4,2-benzodithiazine 1,1-dioxide derivatives with appropriate diamines were investigated. Depending on the reaction conditions 2-mercaptobenzenesulfonamide derivatives or their oxidation product disulfides were obtained. All the compounds were tested at the US National Cancer Institute (Bethesda) for their in vitro anticancer and anti-HIV activities. The highest sensibility against leukemia cell lines was found for bis[2-(6-chloro-4-phenyl-3,4-dihydroquinazolin-2-yl)aminosulfonyl-5-chloro-4-(4-R 2 -phenylcarbamoyl)phenyl]disulfides (R 2 =H or Cl). The results of anti-HIV tests displayed moderate activity of N -(pirydo[3,2- d ]imidazol-2-yl)-2-mercaptobenzenesulfonamide.