Synthesis and structure-activity relationship studies of substituted isoquinoline analogs as antitumor agent

A number of substituted isoquinolin-1-ones, possible bioisosteres of the 5-aryl substituted 2,3-dihydroimidaz[2,1-a]isoquinolines, were synthesized and tested for their antitumor activity against five different human tumor cell lines.O-(3-hydroxypropyl) substituted compound (15) exhibited the best antitumor activity which is 3–5 times better than 5-[4′-(piperidinomethyl) phenyl]-2,3-dihydroimidazo[2,1-a]isoquinoline (1).     

Synthesis and evaluation of anticancer activity of some imidazothiazolyl,imidazobenzothiazolyl and dihydroimidazothiazolyl coumarins

A series of 6-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]thiazoles (1), 2-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]benzothiazoles (2) and 3-(2H-1-benzopyran-2-one-3-yl)-5,6-dihydroimidazo[2,1-b]thiazoles (3) have been synthesized and evaluated for anticancer activity in vitro. The compounds showed very good activity against different tumor cell lines.     

5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents

A series of substituted 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles were synthesized and evaluated in the rat adjuvant-induced arthritis and mouse oxazolone-induced contact sensitivity assays to determine the potential of these compounds for use as immunoregulatory antiinflammatory agents. This class of compounds was derived by combining salient structural features of the antiinflammatory agent flumizole and the immunoregulatory drug levamisole. Unlike the latter two, a number of compounds in the target series were found to possess the desired combination of activities. Exploration of structure-activity relationships in the adjuvant-induced arthritic rat assay revealed that optimal potency was exhibited by symmetrically substituted 5,6-diaryl compounds having one of the following alkyl heteroatom or halogen functions at the para position: methoxy, ethoxy, methylthio, N-ethyl-N-methylamino, fluoro, or chloro. Scrambling of these two substituent classes to yield the asymmetrically substituted 5,6-diaryl compounds resulted in potent activity only with the 5-alkyl heteroatom, 6-halo-substituted regioisomers. However in the oxazolone-induced contact sensitivity assay, no consistent relationship of variation in activity with structural change was apparent. The initial target compound 5,6-bis(4-methoxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole (1) was compared with its progenitors in additional models of inflammation and immunoregulation.     

Synthesis of some 3,4-disubstituted-6,7-dihydro-imidazo[2,1-b][1,3]thiazole and 3,4-disubstituted-7,8-dihydro-6H-imidazo[2,1-b][1,3]thiazine derivatives and evaluation of their cytotoxicities against F2408 and 5RP7 cells

This article describes the synthesis of 3,4-disubstituted-6,7-dihydro-imidazo[2,1-b][1,3]thiazoles and 3,4-disubstituted-7,8-dihydro-6H-imidazo[2,1-b][1,3]thiazines, having substituted or nonsubstituted phenyl rings at the 5,6 and 2,3 positions, respectively, their cytotoxic effects through noncancer (F2408) and cancer (5RP7) cells, and their detailed ¹H- and ¹³C-nuclear magnetic resonance (NMR) spectral characterization. The title compounds were obtained by the cyclization of 4,5-diaryl-imidazole-2-thione and dihaloalkane (i.e., 1,2-dihaloethane or 1,3-dihalopropane), in the presence of potassium carbonate (K₂CO₃) in N,N-dimethyl formamide (DMF). 4,5-Diaryl-imidazole-2-thione was prepared by condensation of α-hydroxyketones (acyloins), which were obtained by treating aldehydes with cyanide, with thioureas in AcOH. The structure of imidazo[2,1-b][1,3]thiazole and imidazo[2,1-b][1,3]thiazine derivatives was confirmed by infrared (IR), ¹H-NMR, and ¹³C-NMR. The cytotoxicities of the synthesized compounds on both of noncancer (F2408) and cancer (5RP7) cells were measured by 3-(4,5-dimethyl-thiazollyl-2)-2,5-diphenyltetrazolium (MTT) assay. In the presence of only lower doses of compounds 9 and 11, bearing methyl or methoxy substituents on the phenyl ring of imidazo[2,1-b][1,3]thiazole scaffold, the cytotoxic effect was higher on 5RP7 cells than control cells after 24 h.     

Microwave-assisted synthesis and antimicrobial activity of some imidazo[2,1-b][1,3,4]thiadiazole derivatives

A simple and efficient method was developed for the synthesis of 2,6-disubstituted-imidazo[2,1-b][1,3,4]thiadiazoles under microwave (MW) activation using 2-amino-5-substituted-1,3,4-thiadiazoles and appropriate bromo ketones as materials. All reactions demonstrated the benefits of MW reactions: convenient operation, short reaction time, and good yields. All derivatives were characterized by IR, NMR, and Mass spectroscopy. Antibacterial and antifungal activity was performed using cup plate method against Staphylococcus aureus, Klebsiella, and Candida albicans microorganisms. 2-(4-nitro benzyl)-6-(4-bromo phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Ce) was the only derivative which showed activity against Klebsiella at low micromolar concentration (5?μg/ml) with moderate zone of inhibition. And 2-(4-nitro benzyl)-6-(4-fluoro phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Cf) as the most potent antifungal active derivative at 50?μg/ml against C. albicans on comparison to standard fluconazole.     

Synthesis and structure-activity relationship studies of 2,3-dihydroimidazo[2,1-a]isoquinoline analogs as antitumor agents

5-Aryl-2,3-dihydroimidazo[2,1-a]isoquinolines were reported to have strong antitumor activity and one of the derivatives such as 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a] isoquinoline (1, SDZ 62–434) was found to be more effective than the clinical cytostatic agent edelfosine (2) inin vitro andin vivo assays. Currently SDZ 62–434 is in clinical trials in Europe. The structure-activity relationship studies of SDZ 62–434 showed that compounds with substitution on ring A were less active than the lead compound. Ring B in SDZ 62–434 was essential for the activity because compounds without B ring had no antitumor activity. Among the 3-arylisoquinolin-1-one derivatives, 3-[4′-(piperidonomethyl)phenyl] substituted analog had no antitumor activity but simple phenyl substituted compound, such as4, showed the most potent antitumor activity in various human tumor cell lines.     

Synthesis and Activity Evaluation of 2-(1-naphtho[2,1-b]furan-2-yl-carbonyl)-3,5-disubstituted-2,3-dihydro-1H-pyrazoles

Ethyl naphtho[2,1-b]furan-2-carboxylate (2) on reaction with hydrazine hydrate in presence of acid catalyst in ethanol medium affords naphtho[2,1-b]furan-2-carbohydrazide (3). The reaction of substituted acetophenones (4a-c) with aromatic aldehydes (5a-e) produces chalcones (6a-o) via the Claisen condensation. The reaction of naphtho[2,1-b]furan-2-carbohydrazide (3) with chalcones (6a-6o) in presence of acetic acid as catalyst in dioxane produces 1-(naphtho[2,1-b]furan-2-yl-carbonyl)-3,5-disubstituted-2,3-dihydro-1H-pyrazoles (7a-o). The structures of newly synthesized compounds have been established by elemental analysis and spectral studies. The compounds 7a-o have been evaluated for their antimicrobial activity and some selected compounds evaluated for antiinflammatory, analgesic, anthelmintic, diuretic and antipyretic activities.     

Synthesis of 6,7-dialkoxy-2-arylmethylidene-2,3- dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol-3-ones exhibiting anti-inflammatory activity

New 6,7-dialkoxy-2-arylmethylidene-2,3- dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol-3-ones (3a-h, 4b, c, e, g) were synthesized from 2-(5,6-dialkoxy-1H-benzo[d]imidazol-2-ylsulfanyl)acetic acids (1, 2) and corresponding aromatic aldehydes in acetic anhydride. The compounds 3e, f and 4b, g were also synthesized from corresponding aromatic aldehydes and 6,7-dialkoxy-2,3-dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol -3-ones (5, 6) obtained by the cyclization of the acids 1 and 2 in acetic anhydride. The synthesized compounds 3a-h and 4b, c, e, g exhibit anti-inflammatory activity.     

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a]pyrimidone-(6) aus 2-Acetoacetylamino-imidazo[2,1-b]-1,3,4-thiadiazolen

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones by Cyclisation of 2-(Acetoacetylamino)-imidazo[2,1-b]-1,3,4-thiadiazoles The 2-acetoacetylamino-6-methyl- (or -aryl) imidazo[2,1-b]-1,3,4-thiadiazoles 1, 2a–f cyclise on heating in polyphosphoric acid (PPA) to yield the tricyclic 2,8-dimethyl- or 2-aryl-8-methyl-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones 3, 4a–f . Only 4c inhibits the growth of vaccinia viruses. The other compounds have no antiviral activity.     

Synthesis of 2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepines and their oxidative ring contraction into 1-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzimidazoles

Syntheses of novel 5-aryl-2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepine derivatives 3a-g were performed by reacting 2-(2-aminoarylimino)imidazolidines 1a-b with corresponding aryl aldehydes. The compounds 3 incorporating aminal group upon treatment with 2,3-dichloro-5,6-dicyano-1,2-benzoqinone (DDQ) underwent the oxidative ring contraction to give 1-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-benzimidazoles 4a-g. Reactions of the compounds 1a-c with carbonyldiimidazole (CDI) afforded novel 2,3,5,6-tetrahydro-1H-imidazo[2,1-b] [1,3,5]benzotriazepin-5-ones 5a-c which when heated in boiling methanol gave the corresponding 1-(4,5-dihydro-1H-imidazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-ones 6a-c. Radioligand binding studies using rat central imidazoline I2 receptors and alpha2-adrenoceptors demonstrated that benzimidazoles 4a-g display a low affinity (microM) for these receptors while benzimidazol-2-ones 6a-b elicited a moderate affinity for I2 receptor with Ki values of 490 and 220 nM, respectively.     

Potential antitumor agents. 37. Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline

This paper reports synthesis and antitumor activity of new guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline. The compounds were tested as potential antitumor agents at the National Cancer Institute. The effect of the guanylhydrazone of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde (41) was investigated, and it was found to be an inhibitor of Complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60.     

Chemical and pharmacological research on derivatives of 1H-naphto/2,1-b/pyran. IV. Substituted 1-oxo-3-dialkylamino-1H-naphto/2,1-b/pyrans]

Reaction of N,N-dialkylethoxycarbonylacetamides with substituted beta-naphthols in 3 or 6 or 7 positions with halogen, alkyl, methoxycarbonyl, methoxyl, ethoxyl in the presence of phosphorus oxychloride, led to the formation of 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans bearing substituents in 5 or 8 or 9 positions, respectively. Moreover, on account of the chemical nature of such substituents, suitable chemical transformations of these compounds afforded some other 1H-naphtho[2,1-b]pyran derivatives. Pharmacological tests showed that anticonvulsant activity was improved by introduction of methoxy or ethoxy group in 9 position of several 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans.     

Inotropic polyazapentalene sulmazole analogues.

Aryl substituted 1H-imidazo[1,2-a]imidazole 8, imidazo[2,1-b]thiazole 9, 1,4-dihydroimidazo[4,5-d]imidazole 11, and 1(2),4-dihydroimidazo[4,5-c]pyrazoles 12-17 have been prepared. An X-ray crystallographic study confirmed the structure of 8 and showed this analogue to exist as the 1H-tautomer. These heterocycles were evaluated as inotropic agents and analogues 12, 15, and 17 found to display inotropic properties which were less potent in vitro, but more potent in vivo, than those of sulmazole. Structure-activity relationships are discussed.     

Chemical and pharmacological research on pyran derivatives. XIV. 3-alkylaminoaphtho/2,1-b/pyran-1-ones and derivatives]

3-Alkyl(phenyl)aminoaphtho[2,1-b]pyran-1-ones (III) were prepared from N-alkyl or N-phenylethoxycarbonylacetamides and 2-naphthol in the presence of phosphorus oxychloride, in order to evaluate their pharmacological activity on the CNS in comparison with previously described 3-dialkylaminoaphtho[2,1-b]pyran-1-ones. Compounds (III) gave 2-morpholinomethyl derivatives as well as N-acetyl and N-ethtoxycarbonyl derivatives. The reaction of (III) in which R = alkyl and N,N-dimethylformamide-POCl3 afforded 2-formyl derivatives and in some cases also 8-alkyl-9,10-bisdimethylaminoaphtho[1',2':5,6]pyrano[2,3-b]pyrrol-11(8H)-ones; when R = phenyl, only naphtho[1',2':5,6]pyrano[2,3-b]quinolin-14-one was obtained from the same reaction. Pharmacological evaluation showed that compounds (III) had a weak CNS depressant activity. Some of them also exhibited antagonist effect on reserpine-induced blepharospasm and hypothermia and on metrazole-induced seizures in the mouse. Within the limits of these activities a special behavior was found for the compound 3-ethylaminoaphtho[2,1-b]pyran-1-one [(III b) - K 12479].     

Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.     

Syntheses in the series of methyl-2-furylketone

2-(5-Nitro-2-furyl)-substituted imidazo-[1,2-b]-benzothiazole and imidazo-[1,2-a]-pyridine, 6-(5-nitro-2-furyl)-substituted 3-(2-furyl)-imidazo-[1,2-b]-1,2,4-triazine, 2-methyl- and 2-(2-furyl)-imidazo-[2,1-b]-1,3,4-thiadiazoles and also 2,6-di-(5-nitro-2-furyl)-imidazo-[2,1-b]-1,3,4-thiadiazole were obtained from bromomethyl-5-nitro-2-furyl ketone and the corresponding heterocyclic amines with amidine structure. The greatest antimicrobial effect among the imidazo compounds is exhibited by 2-(5-nitro-2-furyl)-imidazo-[1,2-a]-pyridine but in most cases it has a weaker effect than furazolidone.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 2, pp. 27–31, February, 1967.     

Influence of structural changes in the imidazolidine ring of clonidine on hypotensive activity.

2-(2,6-Dichlorophenylimino)piperimidine with HNO3 (St-404), 2-(2,6-dichlorophenyl)-5,6-dihydroimidazo[2,1-b]thiazole fumarate (compound 44-549) and 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline with HCl (TIQ) were studied with respect to their effects on blood pressure and heart rate in the anaesthetized, normotensive rat following intravenous administration and in the chloralose-anaesthetized cat by means of infusions via the left vertebral artery. St-404 and compound 44-549 possess central hypotensive and bradycardic activities and display modes of action similar to that of clonidine. Central alpha-adrenergic receptors are presumably involved. In the anaesthetized, normotensive rat St-404 is about 3,400 times less active than clonidine, whereas compound 44-549 is 5 times more effective in lowering arterial pressure. The hypotensive effect of TIQ is brought about by a mechanism of action which is different from that of clonidine. The alpha-sympatholytic properties of TIQ suggested previously by others are not confirmed by the experiments presented in this paper.     

Isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole with broad-spectrum anthelmintic activity

A series of isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (tetramisole) is described. The compounds are prepared by the S-alkylation of the thioureas that were obtained either by the reaction of an amine with 6-(3-isothiocyanatophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b] thiazole or by the reaction of an isothiocyanate with 6-(3-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. These derivatives have an improved spectrum of activity over tetramisole and are active against nematodes, cestodes, and trematodes. The structure-activity relationships are discussed.     

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11). The structures of 4-6 and 8-10 were identified by the results of elemental analysis and their IR, 1H-NMR and MS spectra. Additionally, the structure of 11 was confirmed by X-ray diffraction method. Compounds 8-10 and 11 were examined for their antiproliferative activity in vitro against the cells of 5 human cancer cell lines, using SRB or MTT technique. Among tested compounds, only 11 revealed cytotoxic activity in vitro against all cell lines applied with ID50 (inhibitory dose 50%) values lower than 4 microg/mL, which is an international activity criterion for synthetic compounds. All compounds inhibit the proliferation of HL-60 human promyelocytic leukemia cell line.     

Potential antitumor agents. XX (1) 6-anilinoimidazo[2,1-b]thiazoles

The synthesis of 6-anilinoimidazo[2,1-b]thiazoles, related to the well-known antitumor agent amsacrine, is reported. The cytotoxic activity of the new compounds was evaluated on HeLa cells. Compound 3a, the most closely related to amsacrine, was significantly active.