4H-Pyrrolo[1,2-a]thieno[3,2-f] and 4H-pyrrolo[1,2-a]thieno-[2,3-f][1,4]diazepines: Synthesis and Pharmacological Evaluation

As an extension of a previous work, in which a number of 4H-pyrrolo-[1,2-a]thieno[2,3-f][1,4]diazepines were described, a new series of derivatives of the isomeric pyrrolo[1,2-a]thieno[3,2-f]diazepines ring system has been synthesized. The products obtained, together with those reported in the previous paper, were tested for acute toxicity and CNS activity in mice.     

Synthesis and biological activity of condensed derivatives of thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]thiazolo(thiazino,thiazepino)[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidines

Methods for the synthesis of new heterosystems including condensed pyrano[4′,3′:4,5]pyrido[2,3-b]-thieno[3,2-d]thiazolo(thiazino, thiazepino)[3,2-a]pyrimidines, thiazolo(thiazino, thiazepino)[3″,2″:1′,2′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolines, and cyclopenta[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]thiazolo(thiazino)[3,2-a]pyrimidines are developed. The synthesis is carried out on the basis of 1-amino-2-ethoxycarbonylpyrano[4,3-d]thieno[2,3-b]pyridines and -thieno[2,3-b]isoquinolines. Antitumor and anticonvulsant properties of the synthesized products have been evaluated. Compounds possessing low toxicity and moderate biological activity are found. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 3, pp. 17–21, March, 2009.     

Antihypertensive Effect of some Oxazolo[3,2-a]pyridines,Thiazolo[3,2-a]pyridines and Pyrido[2,1-b]oxazines in Conscious Spontaneously Hypertensive Rats

The antihypertensive activity of eighteen oxazolo[3,2-a]pyridine, fhiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference. At a dose of 50 mg kg^?1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6–8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs. Further studies on the mechanism of action of these derivatives might help the determination of better structure–activity correlations and the design, synthesis and evaluation of better antihypertensive agents.     

Synthesis and anticancer evaluation of novel 3,5-diaryl-thiazolo[4,5-d]pyrimidin-2-one derivatives

The 2-oxo analogs of thiazolo[4,5-d]pyrimidine-2-thiones were prepared to study their cytotoxic activity. Five of the newly synthesized compounds were selected by the National Cancer Institute (Bethesda, MD, USA) for a primary in vitro antitumor assay. 7-Chloro-3,5-diphenyl-thiazolo[4,5-d]pyrimidin-2-one (5a) proved to be the most active one among the screened derivatives and was further evaluated in the full panel of 60 cell lines at five different concentrations. The structures of compounds were determined by IR, ¹H-NMR, ¹³C-NMR, X-ray, and elemental analysis.     

Computer analysis of the structure– bronchodilator activity relationship in thiazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole derivatives

Computer-aided analysis of the structure—activity relationship and purposeful design (SARD) of effective bronchodilators in a series of thiazolo[3,2-a]benzimidazole derivatives has been carried out. The reliability of the created mathematical model is 76 – 81% as determined by the level of recognition of the active and inactive “learning” structures with respect to the property under consideration and depends on the particular group of compounds and the employed algorithm. The results of the prediction agree well with the experimental data because almost all (~90%) of the tested thiazolo[3,2-a]benzimidazole derivatives showed the predicted activity.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.     

Synthesis characterization and biological evaluation of some alkoxyphthalimide derivatives of 3-(4-substituted phenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one

A series of 2-N-ethoxyphthalimido 3-(4-substitutedphenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one(7a–e) and 4-(4-substituted phenyl)-2-(N-ethoxyphthalimido amino)-7,7-diphenylimidazo[2′,1′:2,3][1,3]thiazolo[4,5-d] pyrimidin-8(7H)-one (9a–e) have been designed and synthesized starting from thiohydentoin (1). The structure of all synthesized compounds has been established by IR, ¹H NMR, ¹³C NMR and mass studies. These compounds have been screened for antimicrobial activities in order to evaluate the possibility of the derivatives to be used as potential chemotherapeutic agents.     

Anellierte Thiopyrone, 4. Mitt.1): Indeno[1,2-b]-, Indolo[3,2,-b]-, [1]Benzofuro[3,2-b]- und [1]Benzothieno[3,2-b]thiopyrone

Fused Thiopyrones, IV: Indeno[1,2-b]-, Indolo[3,2-b]-, [1]Benzofuro[3,2-b]-, and [1]Benzothieno[3,2-b]thiopyrones The thiopyrones 2 are obtained from the corresponding thiopyranones 1 by dehydration with tritylperchlorate or SeO₂. Treatment of the benzofurane 2d with m-chloroperbenzoic acid (mCPBA) yields the thiopyrone-S, S-dioxide 3d. Starting from the benzothienothiopyrone 2e only one product, the thiophene-sulfone 3e , can be isolated.     

Dihydroisochinolinumlagerung, 32. Mitt.1) 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine

Dihydroisoquinoline Rearrangement, XXXII: 4-Benzyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridines The synthesis of the title compounds 4a–4c was performed via the 4-benzylthieno[3,2-c]pyridines 2a–2c which were obtained by Grignard coupling or by Wittig alkylation of the chlorothienopyridine 1. Compounds 2a–2c were N-methylated to yield 3a–3c which in turn were reduced with LiAlH₄ to give the 4,5-dihydrothieno[3,2-c]pyridines 4a–4c. On treatment of 4a and 4b with dilute acids the disproportionation products 3a, 9a , and 3b, 9b were obtained with 10% yield. Treatment of 4c with dilute acid gave the disproportionation products 3c and 9c as well as the rearrangement product 8c with 30% yield. This shows that compounds other than 1,2-dihydroisoquinolines can rearrange in the same way as 1-benzyl-1,2-dihydroisoquinolines.     

Synthesis and antitumor activity of certain new thiazolo[2,3-b]quinazoline and thiazolo[3,2-a]pyrimidine analogs

A novel series of thiazolo[2,3-b]quinazoline (16–19, 25–28, and 34–37) and cyclohepta[d]thiazolo[3,2-a]pyrimidine (20–23, 29–32, and 38–41) analogs was designed and synthesized. Structure elucidation of the synthesized compounds was attained by the use of H¹ NMR, C¹³ NMR, and mass spectrometry. The obtained compounds were evaluated for their in vitro antitumor activity using the National Cancer Institute’s 60 cell lines’ panel assay that included nine tumor subpanels, namely, leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer cells. Most of the investigated compounds showed a remarkable broad-spectrum antitumor activity. Compounds 19, 28, 32, and 34 proved to be 10-, 15-, 2-, and 7-fold more active than 5-FU, with GI₅₀ MG-MID values of 2.4, 1.5, 11.2, and 3.1 μM, respectively.     

Synthesis and Biological Evaluation of a Series of Substituted Pyrazolo[3,4-d]-1,2,3-triazoles and Pyrazolo[3,4-d]oxazoles

In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles ( 2e–h, 2j, 4b ) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles ( 3a–e ) and pyrazolo[3,4-d]-1,2,3-triazoles ( 2a–d, 4a, 5 ), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a–e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.     

Synthesis and Structural Evaluations of Thiazolo[3,2-a]pyrimidine Derivatives

2-Thioxo-1,2,3,4-tetrahydropyrimidine derivatives 1 were reacted with phenacyl bromide in glacial acetic acid to obtain thiazolo[3,2-a]pyrimidine derivatives. UV-, IR-, and ¹H-NMR spectra and elementary analysis data confirm structures 3. ¹H-{¹H}-NOE techniques showed that the isolated products are H-5 isomers.     

Isochino[3,2-a]phthalazin-5,8-dione

Isoquino[3,2-a]phthalazine-5,8-diones Deoxybenzoin-2,2′-dicarboxylic acid (1) reacts with the hydrazines 4a-d to yield the phthalazinones 8a-d . Heating of 8a in acetic anhydride leads to the isoquino[3,2-a]phthalazinone 9a , which can also be prepared from 2 and 4a via the O, N-acetal 13 . From 1 and 1,2-dimethylhydrazine (4e) the spiro-compound 14 is formed.     

Anellierte Thiopyrone, 5. Mitt.1): Darstellung und Reaktionen von 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[1]-benzothieno[3,2-b]thiopyronen und 3-Formyl-thiopyrono[3,2-b]indolen

Fused Thiopyrones, V: Syntheses and Reactions of 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[2]benzothieno[3,2-b]thiopyrones, and 3-Formyl-thiopyrono[3,2-b]indoles Alternative syntheses of the title compounds are described. The configuration of the oximes, obtained from the aldehydes, is proved. Furthermore the syntheses of the nitriles and the carboxylic acids is presented.     

Thieno[2,3‐d]pyrimidines in the Synthesis of Antitumor and Antioxidant Agents

Dimethyl acetylenedicarboxylate, ethyl propiolate, and E‐dibenzoylethylene react with thienopyrimidines (cyclo‐pentyl, ‐hexyl, and ‐heptyl) derivatives to form thiazolo[3,2‐a]thieno‐[2,3‐d]pyrimidin‐2‐ylidene) acetates, thieno[2,3‐d]pyrimidin‐2‐ylthioacrylates, and thieno[2′,3′:4,5]pyrimido[2,1‐b][1,3]thiazin‐6‐ones, respectively. Reactions proceed via cyclization and thio‐addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep‐G2 cells with IC₅₀ < 20 μM.     

Synthesis and evaluation of in vitro antitubercular activity and antimicrobial activity of some novel 4H-chromeno[2,3-d]pyrimidine via 2-amino-4-phenyl-4H-chromene-3-carbonitriles

Novel 5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dithiones, 5-phenyl-3,5-dihydro-4H-chromeno[2,3-d]pyrimidin-4-ones, 7-phenyl-7,9-dihydro-8H pyrimido[5′,4′:5,6]pyrano[3,2-h]quinolin-8-ones, and 4-amino-5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2-thiones were synthesized form 2-amino-4-phenyl-4H-chromene-3-carbonitrile. The newly synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, Mass spectra, and Elemental analysis. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H ₃₇ Rv and antibacterial activity against Staphylococcus Aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as Gram-positive, Escherichia coli [ATCC-25922], and Pseudomonas aeruginosa [MTCC-441] as Gram-negative bacterial strains and antifungal activity against Aspergillus niger [MTCC-282]. Some of these derivatives exhibited pronounced antitubercular and antimicrobial activities.     

Synthesis and biological evaluation of some novel urea and thiourea derivatives of isoxazolo[4,5-d]pyridazine and structurally related thiazolo[4,5-d]pyridazine as antimicrobial agents

This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7-dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c–d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl)-benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H-thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study.     

Synthesis of novel 4,5-dihydropyrrolo[1,2-a]quinoxalines,pyrrolo[1,2-a]quinoxalin]-2-ones and their antituberculosis and anticancer activity

A facile strategy was developed for the synthesis of biologically important 4,5-dihydropyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a]quinoxalin]-2-ones by treating 2-(1H-pyrrol-1-yl)anilines with imidazo[1,2-a]pyridine-3-carbaldehyde or isatin, using amidosulfonic acid (NH₃SO₃) as a solid catalyst in water at room temperature. The protocol has been extended to electrophile ninhydrin. The catalyst could be recycled for six times without the loss of activity. The compounds were evaluated for their antituberculosis, antibacterial, and anticancer activities. It is worth noting that compounds 3d and 3e demonstrated a minimum inhibitory concentration value of 6.25 µM against Mycobacterium tuberculosis H37Rv, whereas compounds 3d , 3g , 5d , 5e , and 5i showed a remarkable inhibition of A549, DU145, HeLa, HepG2, MCF-7, and B16-F10 cell lines, respectively. Staphylococcus aureus was inhibited by compounds 5b , 5e , 5d , 5g , and 5l at 32 µg/ml.     

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.     

Reaktionen von 2-Amino-imidazo[2,1-b]-1,3,4-thiadiazolen mit Dicarbonsäureestern in Polyphosphorsäure (PPA)

Reactions of 2-Aminoimidazo[2,1-b]-1,3,4-thiazoles with Ethyl Dicarboxylates in Polyphosphoric Acid (PPA) The 2-amino-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 1d,e cyclise on heating in polyphosphoric acid (PPA) with ethyl malonate or ethyl diethylmalonate to yield the 2-aryl-6,8-dioxodihydro-6H-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a] pyrimidines 3d,e or the 7,7-diethyl compounds 4d,e . Compounds 1a – f cyclise in PPA with ethyl succinate or ethyl phthalate to yield the 6-aryl-2-succinimido- or 6-aryl-2-phthalimido-imidazo[2,1-b]-1,3,4-thiadiazoles 5a, b, d-f and 6a – f . Compounds 1d,e were condensed with ethyl oxalate to yield the 2-(ethoxycarbonyl-formylamino)-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 7d,e. Ethyl levulinate with 1d,e in PPA probably forms 6-aryl-2-(2-methyl-5-oxo-Δ³-pyrrolino)imidazo [2,1-b]-1,3,4-thiadiazoles.