Synthesis and cytotoxic evaluation of benzoxazole/benzothiazole-2-imino-coumarin hybrids and their coumarin analogues as potential anticancer agents.

Two series of 2-imino-coumarin based hybrids: 3-(benzoxazol-2-yl)-2H-chromen-2-imines 3-9 (series A-I) and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 10-16 (series A-II), as well as their coumarin analogues: 3-(benzoxazol-2-yl)-2H-chromen-2-ones 17-21 (series B-I) and 3-(benzothiazol-2-yl)-2H-chromen-2-ones 22-28 (series B-II) were prepared as potential antitumor agents. The in vitro cytotoxic potency of the synthesized compounds was evaluated against five human cancer cell lines: DAN-G, A-427, LCLC-103H, RT-4 and SISO, and relationships between structure and anticancer activity are discussed. Among the compounds tested, 3-(benzo[d] oxazol-2-yl)-N,N-diethyl-2-imino-2H-chromen-7-amine (6, series A-I) and 3-(benzo[d]thiazol-2-yl)-6-fluoro-2H-chromen-2-one (26, series B-II) exhibited the most potent cytotoxic activity with IC50 values ranging from <0.01 µM to 1.1 µM. In particular, compound 6 demonstrated remarkable cytotoxicity against the A-427 ovarian cancer, the lung cancer LCLC-103H, urinary bladder cancer RT-4 and cervical cancer SISO cell lines with IC50 <0.01-0.30µM, inducing apoptosis in two representative cell lines.

Synthesis, structure and anticancer activity of novel alkenyl-1,3,5-triazine derivatives.

A series of novel 4-(E)-ethenyl-6-alkylamino-1,3,5-triazin-2-ylamine derivatives 9-17 have been synthesized by a Wittig reaction of corresponding alkyltriphenylphosphonium bromides 5-8 with (hetero)aromatic aldehydes. The E configuration of these alkenes was confirmed by 1H NMR spectroscopic data. All the compounds prepared were screened at the National Cancer Institute (NCI) for their activity against a panel of 56 tumor cell lines and relationship between structure and in vitro antitumor activity is discussed. The most active compounds 14 and 17 showed 50% growth inhibitory activity in low micromolar concentrations against renal cancer A498 cell line and colon cancer cell line COLO 205, respectively.

Synthesis, structure and anticancer activity of novel 2,4-diamino-1,3,5-triazine derivatives.

A series of 2-(4,6-diamino-1,3,5-triazin-2-yl)-2-{[4-(dimethylamino)-phenyl]imino}acetonitriles 19-27 have been synthesized by the reaction of 2-(4-amino-6-alkylamino-1,3,5-triazin-2-yl)acetonitriles 10-15 with p-nitrosodimethylaniline. Unexpectedly, a similar reaction of acetonitriles 10, 14, 15, 17 and 18 with nitrosobenzene led to the formation of 4,6-diamino-N-phenyl-1,3,5-triazine-2-carboxamides 28-32. The in vitro antitumor activity of the compounds obtained has been tested and 2-[4-Amino-6-(4-phenylpiperazin-1-yl)-1,3,5-triazin-2-yl]-2{[4-(dimethylamino)phenyl]imino}acetonitrile (19) having remarkable activity against melanoma MALME-3 M cell line (GI(50)=3.3 x 10(-8) M, TGI=1.1 x 10(-6) M) is a leading candidate for further development.

2-(4,5-dihydro-1H-imidazol-2-yl)indazole (indazim) derivatives as selective I(2) imidazoline receptor ligands.

A series of variously substituted 2-(4,5-dihydro-1H-imidazol-2-yl)indazoles 3a-j and 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5,6,7-tetrahydroindazole 6 were prepared by the regiospecific heteroalkylation of corresponding indazoles 1a-k with 2-chloro-4,5-dihydroimidazole (2). Their affinity to imidazoline I(2) receptors and alpha(2)-adrenergic receptors was determined by radioligand binding assay carried out on P(2) membrane preparations obtained from rat whole brains. 4-Chloro-2-(4,5-dihydro-1H-imidazol-2-yl)indazole (3f, 4-Cl-indazim) showed a 3076-fold difference in affinity for the [(3)H]2BFI-labeled imidazoline I(2) receptors relative to the [(3)H]RX821001-labeled alpha(2)-adrenergic receptors. This highly selective compound should prove to be useful tool in further understanding the functions of the imidazoline I(2) receptors.

Synthesis and antitumor activity of novel 2-amino-4-(3,5,5-trimethyl-2-pyrazolino)-1,3,5-triazine derivatives.

The syntheses and antitumor activities of novel 2-amino-4-(3,5,5-trimethyl-2-pyrazolino)-1,3,5-triazine derivatives 4-38 are described. All the compounds prepared were screened at the National Cancer Institute (NCI) for their activities against a panel of 60 tumor cell lines and relationships between structure and antitumor activity in vitro are discussed. The triazines 11, 16, 20, 23, 23 and 34-38 exhibited modest or fairly high activity against one or more human tumor cell lines. Prominent compound with remarkable activity (log GI50, < - 8.00- - 5.00) to all investigated cell lines and highly potent (log GI50 < - 8.00- - 7.64) against some cell lines of Leukemia (CCRF-CEM, K-562, RPMI-8226, SR), CNS Cancer (SF-539) and Breast Cancer (T-47D) was 2-[2-amino-4-(3,5,5-trimethyl-2-pyrazolino)-1,3,5-triazin-6-yl]-3-(5-nitro-2-thienyl)acrylonitrile (25).

Synthesis, molecular structure and anticancer activity of 1-allyl-3-amino-2-(4-chloro-2-mercaptobenzenesulphonyl)guanidine derivatives.

A series of 3-allylamino-6-chloro-7-R-1,1-dioxo-1,4,2-benzodithiazines (2a-e) was obtained by the reaction of 6-chloro-3-methylthio-1,4,2-benzodithiazine-1,1-dioxides (1a-e) with allylamine. Selective hydrazinolysis of the allylaminobenzodithiazines (2a-e) gave the appropriate 1-allyl-3-amino-2-(4-chloro-2-mercaptobenzenesulphonyl)guanidines (3a-e) in good yields. The reaction of 3a with dimethylsulphate under alkaline conditions provided the methylthio derivative 4. The structures of these compounds were confirmed on the basis of elemental analysis, spectral data (IR, 1H- and 13C-NMR) and X-ray analysis. Screening data indicated that the compounds 3a and 3d exhibited significant in vitro activities against numerous human tumour cell lines, whereas compounds 3b and 3c showed a moderate activity.

Carbon disulfide promoted reactions of 2-chloro-4,5-dihydro-imidazole with some N-nucleophiles.

The reactions of 2-chloro-4,5-dihydroimidazole 1 with o-substituted anilines and azoles promoted by carbon disulfide have been carried out. Ab initio MO calculations were used to elucidate the mechanism of the reaction of 1 with N-nucleophilic reagents. A facile synthesis of 2-(4,5-dihydroimidazol-2-yl)-1H-indazole 3e bearing structural resemblances to 2-BFI, a potent and selective agonist of imidazoline I2 receptors, is also described. Structure of 3e was confirmed by NMR spectroscopy and X-ray analysis.

Synthesis, structure and antiaggregatory effects of some N-(4,5-dihydro-1H-imidazol-2-yl)indoles.

A series of 1-(4,5-dihydro-1H-imidazol-2-yl)indole derivatives was prepared in order to evaluate their antiaggregatory activity in human platelets. The compounds 4a-m were prepared by reacting N-aryl-N-(4,5-dihydro-1H-imidazol-2-yl)hydroxylamines (2a-d) with monosubstituted acetylene derivatives 3a-b. Imidazoline derivatives 4 were further acetylated or sulfonylated to give amides 5a-c and sulfonamides 6a-c and 7a-c, respectively. Eight compounds were taken as representative aryliminoimidazoline analogs. Among them only one, 4m, showed a good concentration-dependent action against the primary or alpha 2-adrenoreceptor mediated phase of noradrenaline-induced aggregation in platelets.

Synthesis, structure, and binding of some 2-imidazolines to rat brain alfa-1 and alfa-2-adrenergic receptors.

A series of novel 2-[(2-aminophenyl)imino]imidazolinium salts 3a-d and N-benzyl-N-(4,5-dihydro-imidazol-2-yl)-O-methylhydroxylamine hydrochloride 7a-c were prepared and their structure was determined by IR and NMR spectroscopic data as well as X-ray analysis of the imidazolinium azide salt 3e. Binding evaluation for both alpha 1- and alpha 2-adrenergic receptors in rat brain preparations of these compounds and the previously described alpha-hydroxy-2-aryliminoimidazolines 11a-d, N-(4,5-dihydroimidazol-2-yl)-1,3-2-oxodihydrobenzimidazoles 12a-b, 2-amino-N-(4,5-dihydroimidazol-2-yl)-benzimidazoles 13a-b, and N-(4,5-dihydroimidazol-2-yl)-indoles 14a-b was performed. Among the compounds tested, 2-[(2-amino-4,5-dichlorophenyl)imino]imidazolinium chloride 3c showed highest binding affinity to alpha 2-adrenoreceptors (Ki = 30 nM).

Synthesis, structural characterization and antitumor activity of novel 2,4-diamino-1,3,5-triazine derivatives.

The syntheses, structural elucidation based on NMR spectroscopy and X-ray analysis of 8 as well as antitumor activities of novel 2,4-diamino-1,3,5-triazine derivatives 5 and 7-22 are described. Screenings performed at NCI showed that most derivatives possessed a moderate to strong growth inhibition activity on various tumor panel cell lines between 0.148 and 56.2 microM concentrations. 2-Amino-6-bromomethyl-4-(3,5,5-trimethyl-2-pyrazoline)-1,3,5-triazine 11 showed the most potent antitumor activity with the mean midpoint values of log(10) GI50, log(10) TGI50 and log(10) LC50 of all tests equal to -5.26, -4.81 and -4.37, respectively and therefore, it can be considered as a lead structure for further development of anticancer agents.

Synthesis, structure, and biological activities of some N-(4,5-dihydro-1H-imidazol-2-yl)-1,3-dihydrobenzimidazole derivatives.

A series of novel N-(4,5-dihydroimidazol-2-yl)-1,3-dihydrobenzimidazole derivatives 2a-d, 3a-d and 4a-p were prepared and their structure was determined by IR and NMR spectroscopic data as well as X-ray analysis of carbonitrile 2a. The compounds were studied as potential inhibitors of the human blood platelet aggregation induced by adrenaline or ADP. Compounds of type 3 proved efficacious for the reduction of arterial blood pressure upon intravenous administration to normotensive rats.

Synthesis and biological activities of some 7,8-dihydroimidazo[1,2-a]-1,3,5-triazine derivatives.

The alkylation of 7,8-dihydroimidazo[1,2-a]-1,3,5-triazine-2,4-(3H,6H)-dithione [I] with 2-chloro-N-arylacetamides gave 2-alkyltio derivatives [III]. Further reactions of 2-(alkyltio)-7,8-dihydroimidazo[1,2-a]-1,3,5-triazine-4(6H)- thiones [III] or [IV] with aryl isothiocyanates, sulfochlorides or 2-bromo-1-phenylethanone afforded corresponding B-substituted products [V,VI,VII].

Synthesis, transformations and tuberculostatic activity of 1-(N-aroylthiocarbamoyl)imidiazolidine-2-thiones.

Series of 1(N-aroylthiocarbamoyl)imidiazolidine-2-thiones and 3-aroylimino-5,6-dihydro-3H-imidazo[2,1-c](1,2,4) dithiazoles were prepared for antituberculostatic screening. Dithiobiuret was transformed into N1-disubstituted thiocarbamoyl 1-N-aroylthiocarbamoyl ethylenediamines by reacting with secondary amines or hydrazine derivatives.

A search for new antihypertensive agents. II. Circulatory activity and selection of structures among 2-methylbenzimidazole derivatives.

A series of twelve 2-methylbenzimidazole derivatives was prepared and their effect on the contraction of isolated rat tail artery, on beating rate and amplitude of isolated rat heart atria, on human blood platelet aggregation, and on blood pressure in urethane-anesthetized normotensive rats were tested. Numerical measures of pharmacodynamic activity were quantitatively related to the changes in chemical structure of the agents. Conclusions are drawn about the mechanism of pharmacodynamic action of 2-methylbenzimidazole derivatives, which is not executed directly through the adrenergic system. The further direction of synthesis is established basing on the results obtained.