Synthesis of New 2,3-Disubstituted 4 (3H)-Quinazolones and Related Products as Potential Antiviral Agents

Sixteen new 2,3-disubstituted 4 (3H)quinazolone derivatives were synthesized and evaluated for their antiviral activities against Gomphrena mosaic and Sunnhemp rosette virus. Most compounds show antiviral activity against Gomphrena mosaic virus.     

Synthesis and antimicrobial activity of [6′-methyl-4′-methoxy-2-oxo-2H-[1]-benzopyran)-2″,4″-dihydro-[1″, 2″, 4″]-triazol-3″-one and 3″-phenyl-thiazolidin-4″-one-phenoxymethyl derivatives of dipyranoquinoline

A series of bioactive 3H,7H,8H,11H-9-[(5″-(6′-methyl-2-oxo-2H-[1]-4′-benzopyranoxy)-2″,4″-dihydro-[1″,2″,4″]-triazol-3″-one)methyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (4) and 3H,7H,8H,11H-9-[(2′-(3″-phenyl-thiazolidin-4″-one)-phenoxymethyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (7) analogs of 3H,7H,8H,11H-9-bromomethyl-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (1) have been synthesized and evaluated for their antibacterial activity against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (S. typhi and E. coli). Pyranoquinolines with triazole and thiazolidine moieties exhibited promising antibacterial activity. The structures of all synthesised compounds were confirmed on the basis of analytical and spectral data.     

Oxazepines and Thiazepines,XXVII: Chemical Transformations of 2,3-Dihydro-2-phenyl-1,4-benzoxazepin-5(4H)-one

N-Alkyl ( 2 - 11 ) and N-acyl ( 18 - 30 ) derivatives of 2,3-dihydro-2-phenyl-1,4-benzoxazepin-5(4H)-one ( 1 ) have been synthesized. 4-Alkyl-2,3-dihydro-2-phenyl-1,4-benzoxazepin-5(4H)-thiones 12 - 15 arose from compounds 2, 3, 5 , and 6 with Lawesson's reagent. Bis-[2,3-dihydro-2-phenyl-1,4-benzoxazepin-5(4H)-onyl]-alkanes 16 and 17 were prepared from 1 and dihaloalkanes.     

Leishmanicidal Evaluation of Novel Synthetic Chromenes

In the present paper, twelve chromenes were synthesized by coupling of 2,2,8,8‐tetramethyl‐8H‐pyrano[2,3‐f]chroman‐4‐one 1 with various aryl and benzylmagnesium chlorides. The synthetic compounds were examined for in‐vitro activity against Leishmania major, and some of them displayed efficient anti‐leishmanial activity. Among the compounds tested, compounds 9 (4‐(2‐chloro‐benzylidene)‐2,2,8,8‐tetramethyl‐3,4‐dihydro‐2H,8H‐pyrano[2,3‐f]chromene 9a and 4‐(2‐chloro‐benzyl)‐2,2,8,8‐tetramethyl‐2H,8H‐pyrano[2,3‐f]chromene 9b ) were the most active with an inhibitory activity of 73.4%.     

Mehrcyclische Azine mit Heteroatomen in 1- und 3-Stellung, 40. Mitt. Synthese heterocyclischer Immunmodulatoren, 2. Mitt.: 3-Mercaptoalkylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione: Synthese und Prüfung auf immunstimulatorische Wirksamkeit

Polycyclic Azines, XL: Synthesis of Heterocyclic Immunomodulators, II: 3-Mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones: Synthesis and Test for Immuno-stimulating Activity A series of 3-mercaptoalkylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones 3 was prepared and their immuno-stimulating activity was examined. The title compounds were obtained conveniently by hydrolytic ring cleavage of fused thiazolo- or 1,3-thiazino-thicnopyrimidines 1 under alkaline or acidic reaction conditions. The ms fragmentation of the thieno[2,3-d]pyrimidine-2,4-diones 3 is discussed. In the delayed type hypersensitivity (DTH) test some compounds 3 showed immuno-stimulating activities in the range of isoprinosine.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5‐HT2A,Dopamine and Histamine H1 Receptor Ligands

LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D₁/D₅ receptors and the serotonin 5‐HT_2A receptor. This compound consists of a ten‐membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz‐indolo‐azecine, both rings were removed and replaced with a 1H‐pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3‐g]indolizine, pyrrolo[3,2‐a]quinolizine rings and their corresponding dimethylpyrrolo[2,3‐d]azonine, and dimethylpyrrolo[2,3‐d]azecine were synthesized to be evaluated for their activity at the 5‐HT_2A and dopamine D₁, D_2L, D₄, D₅ receptors in relation to LE 300 . In addition, their activity at the H₁‐histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3‐g]indolizine 7 and pyrrolo[3,2‐a]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3‐d]azonine 11 and pyrrolo[2,3‐d]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5‐HT_2A and histamine H₁ receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1H‐pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine‐type compounds.     

Umsetzung von 1,2-Dihydro-3-indazolon mit ω-Dialkylaminoalkylhalogeniden und α,ω-Dihalogenalkanen

Reaction of 1,2-Dihydro-3-indazolone with ω-Dialkylaminoalkyl Halides and α, ω-Dihalogenalkanes The reaction of the potassium salt of 1,2-dihydro-3-indazolone with ω-dialkylaminoalkyl halides in anhydrous dioxane leads to basic lactim ethers, which are analgesics. On the other hand two basic compounds are formed, when α, ω-dihalogenopropanes participiate. Compound 1 was identified as 3,4-dihydro-2H-[1,3]oxazino[2, 3-b]indazole and compound 2 as 2,3-dihydro-lH-pyrazolo[1,2-a]indazol-9-one. Compound 2 is reduced by LiAlH₄, to 2,3-dihydro-lH, 9H-pyrazolo[1, 2-a]indazole ( 5 ).     

Oxazepines and Thiazepines,XXV: Chemical Transformations of 2,3-Dihydro-1,5-benzothiazepin-4(5H)-ones

2,3-Dihydro-1,5-benzothiazepine-4(5H)-thiones 13-22 were prepared by the reaction of the appropriate 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones with Lawesson's reagent. N-Acyl ( 23-25 ) and N-alkyl ( 26-28 ) derivatives have also been synthesized. Oxidation with 3-chloroperoxybenzoic acid afforded sulfoxides 29-32 , and sulfones 33-40 were obtained by using H₂O₂ as an oxidizing agent.     

Constituents of the leaves and roots of Ligularia stenocephala MATSUM. et KOIDZ.

Constituents of the leaves and roots of Ligularia stenocephala MATSUM. et KOIDZ. (Compositae) were investigated. Three compounds, (2E,6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaen-1-ol, (3E,6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyl-3,6,10,14,18,22-tetracosahexaen-2-ol and neophytadiene, were isolated from the leaves of L. stenocephala. Six compounds, 5-acetyl-6-hydroxy-2α-isopropenyl-3β-methoxy-2,3H-benzofuran, 3β-acetoxy-6-acetyl-5-hydroxy-2α-isopropenyl-2,3H-benzofuran, p-hydroxybenzaldehyde, vanillin, 4-hydroxyacetophenone and 4-hydroxy-3-methoxyacetophenone, were isolated from the roots of L. stenocephala. The structures were determined on the basis of spectral data.     

Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2, and H3 receptors

Histamine is a transmitter that activates the four receptors H₁R to H₄R. The H₃R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have the selectivity for the H₃R over the H₄R. Here, we describe their pharmacological properties at the human H₁R and H₂R in parallel with the H₃R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H₃R‐induced histamine responses, but no inhibition of H₂R‐induced responses was seen. Three compounds were weakly able to inhibit H₁R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N‐methyl group improves H₃R affinity while the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.     

Synthesis,analgesic, anti‐inflammatory and ulcerogenic index activities of novel 2‐methylthio‐3‐substituted‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones

A variety of novel 2‐methylthio‐3‐substituted amino‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones were synthesized by reacting 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one with different aldehydes and ketones. The starting material 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one was synthesized from 2‐amino‐3‐carbethoxy‐4,5‐dimethyl thiophene. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic index activities in Wistar rats. The compound 2‐(1‐ethylpropylideneamino)‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one (AS2) showed the most potent analgesic activity of the series. It also showed more potent anti‐inflammatory activity when compared to the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic potential when compared to aspirin. Drug Dev Res 68:134–142, 2007. © 2007 Wiley‐Liss, Inc.     

Synthese von 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-onen und 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-on

Synthesis of 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-ones and 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one The title compounds 4 and 6 were prepared by Fischer indole synthesis. 4a is substituted in 10-position by reaction with bromine in glacial acetic acid. A fast ring inversion is observed for the azepine ring in 4 and 6 .     

H2-antihistaminics, LX: ketene N,N-acetals with H2-antihistaminic activity

H₂-Antihistaminics, IX: Ketene N, N-acetals with H₂-Antihistaminic Activity The ketene N, N-acetals (keteneaminals) 4a-e were prepared and tested for their H₂-antihistaminic activity.     

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.     

Novel benzimidazo[2,1-c][1,4]thiazinone derivatives with potent activity against HSV-1

The synthesis of new 2‐carboxymethylsulfanylmethyl‐1H‐benzimidazole and 1,3‐dihydro‐4H‐benzo[4′,5′]imidazo[2,1‐c][1,4]thiazine‐4‐one‐8‐carboxylic acid derivatives was investigated. The antiviral activity of compounds 1–14 was tested against the herpes simplex virus 1. Compounds 5 and 14 showed potent activity as they inhibited virus propagation by 94.7% and 91.3% at a dose of 50 µg, respectively. Compounds 5 and 14 showed higher potency than Acyclovir at doses of 20 µg and 50 µg.     

Biological evaluation of novel 1,4-dithiine derivatives as potential antimicrobial agents

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.     

Reaktionen an Heterocyclen mit 2-Acyl-2-propenon-Teilstruktur, 2. Mitt.1,2) Pyrido[2,3-d]pyrimidine aus 4-Oxo-4H-chromen-3-carboxaldehyden und 4-Aminouracilen

Reactions of Heterocycles Containing a 2-Acyl-2propenone Structure, II: Pyrido[2,3-d]pyrimidines from 4-oxo-4H-chromene-3-carbaldehydes and 4-Aminouraciles Depending on the solvent, 4-oxo-4H-chromene-3-carbaldehydes 1 react with 4-aminouraciles 2 , 6 and 10 to yield pyrido[2,3-d]pyrimidines of different structures. In dipolar aprotonic solvents the 6H-[l]benzopyrano[3,4-g]pyrido[2,3-d]pyrimidines 4 and 8 are formed. In hot glacial acetic acid the 6-(2-hydroxybenzoyl)pyrido[2,3-d]pyrimidines 5 , 9 and 14 are obtained.     

Anellierte Thiopyrone, 2. Mitt. Thiopyrano[3,2-b]indol-4(5H)-on- und Thiopyrano[2,3-b]indol-4(9H)-on-2-carbonsäuren

Fused Thiopyrones, II; 2-Carboxylic Acids of Thiopyrano [3,2-b]indol-4(5H)-one and Thiopyrano[2,3-b]indol-4(9H)-one 3-Indolylthiofumaric acids 2 are cyclized by polyphosphoric acid (PPA) to yield the isomeric title compounds 6 and 8 .     

Derivatives of 3-aminothieno(2,3-d)pyrimidine and of 3-amino(1)benzothieno(2,3-d)pyrimidine (author's transl)]

Derivatives of 3-Aminothieno[2,3-d]pyrimidine and of 3-amino[1]benzothieno[2,3-d]pyrimidine Derivatives of 3-aminothieno[2,3-d]pyrimidin-4(3H)-one and of 3-amino-5,6,7,8-tetrahydro[1]-benzothieno[2,3-d]pyrimidin-4 (3H)-one, both carrying basic substituents at position 2 (general formulae I and II ), were synthesized in an one-step reaction from the corresponding 2-acylamino-thiophene-(or-benzo[b]thiophene)-3-carboxylates with hydrazine.