2-Phenylimidazo[1,2-b]pyridazine derivatives highly active against Haemonchus contortus

A series of 2-phenylimidazo[1,2-b]pyridazine derivatives were synthesized and evaluated for their in vitro anthelmintic activity against Haemonchus contortus. The most active compounds had in vitro LD₉₉ values of 30 nM, which is comparable to that of the benchmark commercial nematocide, Ivermectin.     

Synthesis and cytotoxicity of 8-cyano-3-substitutedalkyl-5-methyl-4-methylene-7-methoxy-3,4-dihydropyrido[4,3-d]pyrimidines

Synthesis and cytotoxicity of 11 4-methylene pyrido[4,3-d]pyrimidines 5a-k were described. Cytotoxicity assay results showed that some compounds had much stronger antitumor activity than Fluorouracil against KB cell lines. The most active compound 5i exhibited high potency against KB, CNE2, MGC-803 cell lines with IC(50) values of 0.48, 0.15, 0.59 μM, respectively. The preliminary structure-activity relationships indicated that the introduction of benzyl groups bearing electron-donating function groups is favorable for the activity.     

Regioselectivity in the glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol

The glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) and its 3-benzylsulfanyl and 3-methylsulfanyl derivatives with different glycosyl halides 2-4 has been studied in presence of base. The S-glycosides 5-7 were obtained in the presence of triethylamine, whereas the respective S,N⁴-bis(glycosyl) derivatives 8-10 were synthesized in the presence of potassium carbonate; the S,N²-bis(glycosyl) isomer 11 could also be isolated in the case of the galactosyl analog. Similarly, after protecting 1 as 3-benzyl(methyl)sulfanyl derivatives 12 or 13, the N⁴-glycosyl analogs 14-19 as well as minor amounts of S,N²-bis(galactosyl) isomers 20 and 21 were formed. The theoretical calculations using AM1 semiempirical methods agreed with the experimental results. Microwave irradiation (MWI) led to higher yields in much less time than the conventional methods, and no change in regioselectivity has been noticed.     

1,2,4-triazolo[4,3-a]pyrimidines: a new kind of ligands. Structure of the silver(I) dimer with the 7-oxo derivative

This paper describes the silver dinuclear complex [Ag₂L₂(NO₃)₂] · 2H₂O, where L represents the bridging ligand 7,8-dihydro-7-oxo-1,2,4-triazolo[4,3-a]pyrimidine, this being the first example of a coordination compound of a 1,2,4-triazolo[4,3-a]pyrimidine derivative. As a difference with the most studied 1,2,4-triazolo[1,5-a]pyrimidine derivatives, the coordination takes place through the contiguous nitrogen atoms of the triazole ring, closing a six member Ag₂N₄ core with a higher intermetallic distance, 3.4791(3) Å. Linear coordination of silver is not possible in this geometry, so flat trigonal coordination involving also the nitrate counteranion is found instead.     

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC₅₀ 0.037, 0.044 and 0.042?μM, respectively, while IC₅₀ of thiourea is 20.9?μM.     

Synthesis,modeling and biological evaluation of some pyrazolo[3,4-d]pyrimidinones and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones as anti-inflammatory agents

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.     

A newly synthesized 6-methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-one for potential inhibitor of adenosine A1 receptor: a combined experimental and computational studies

Abstract

6-Methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-onehas been synthesized, characterized by spectroscopic techniques (FT-IR, ¹H and ¹³C NMR) and finally the structure was confirmed by single crystal X-ray diffraction studies. In the title molecule, C₆H₇N₅O, the 7-membered ring adopts a bowl-like conformation. In the crystal, the molecules form stacks along the c-axis direction through offset π-stacking interactions between the 5-membered rings and C–H···N hydrogen bonds. The stacks are associated via a combination of N–H···N, C–H···O and C–H···N hydrogen bonds. Further, the Hirshfeld surface analysis reveals the nature of molecular interactions and the fingerprint plot provides information about the percentage contribution from each individual molecular contact to the surface. In addition, due to its biological interest the target molecule adenosine A1 receptor was found based on Structural Activity Relationship (SAR) analysis and, further, subjected into molecular docking and molecular dynamics analysis to understand the binding interaction and stability of the molecule in adenosine A1 receptor system. Furthermore, the Density Functional Theory (DFT) calculations were carried for free compound and the compound in active site (single point DFT), to know the internal stability.

Communicated by Ramaswamy H. Sarma     

Synthesis and bioevaluation of 6-chloropyridazin-3-yl hydrazones and 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines as cytotoxic agents

An efficient synthesis of a series of 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines is described via intramolecular oxidative cyclization of various 6-chloropyridazin-3-yl hydrazones with iodobenzene diacetate. The structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, NMR (¹H and ¹³C) and mass spectral data. All the thirty three compounds 3a-q and 4b-q synthesized in the present study were evaluated for their in vitro cytotoxic activities against two Acute Lymphoblastic Leukemia (ALL) cell lines named, SB-ALL and NALM-6, and a human breast adenocarcinoma cell lines (MCF-7). The results revealed that triazoles 4 exhibit better cytotoxicity than their hydrazone precursors 3. Among triazoles, compounds 4f, 4j and 4q exhibited potent cytotoxic activity against SB-ALL and NALM-6 with IC₅₀ values in the range of ∼1.64–5.66 μM and ∼1.14–3.7 μM, respectively, compared with doxorubicin (IC₅₀ = 0.167 μM, SB-ALL). Compounds 4f, 4j and 4q were subjected to apoptosis assay after 48 h treatment and these compounds induced apoptosis of NALM-6 cells via caspase 3/7 activation. Results revealed that compound 4q represents potential promising lead.     

Synthesis of some novel 6-benzyl(or substituted benzyl)-2-beta-D-glucopyranosyl-1,2,4-triazolo[4,3-b][1,2,4]triazines as potential antimicrobial chemotherapeutics

Glucosidation of the new 8-amino-6-benzyl(or substituted benzyl)-2,8-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazin-7(3H)-ones (3a-d) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide 4 gave the corresponding N-glucosides 5a-d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7-12. Antimicrobial activity of compounds 5a-c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.     

Novel bifunctional alkylating agents, 5,10-dihydropyrrolo[1,2-b]isoquinoline derivatives, synthesis and biological activity

A series of linear pyrrolo[1,2-b]isoquinoline derivatives was synthesized for antitumor evaluation. The preliminary antitumor studies reveal that both bis(hydroxymethyl) and their bis(alkylcarbamate) derivatives show significant antitumor activity in inhibiting various human tumor cell growth in vitro. 1,2-Bis(hydroxymethyl)-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (20a) was selected for antitumor studies in animal models. The results show that this agent can induce complete tumor remission or significant suppression in nude mice bearing human breast (MX-1) xenograft and ovarian (SK-OV-3) xenografts, respectively. Alkaline agarose gel shifting assay showed that 20a is able to cross-link with DNA. Studies on the cell cycle inhibition revealed that this agent induces cell arrest at G2/M phase. The results warrant further antitumor investigation against other human tumor growth in animal models.     

Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones and evaluation of anticancer potential towards human cervix adenocarcinoma

A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cycloisomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These compounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC₅₀ value of 0.22 μM.     

Synthesis and biological evaluation of novel pyrazolo[4,3-b]oleanane derivatives as inhibitors of glycogen phosphorylase

Eighteen pyrazolo[4,3-b]oleanane derivatives have been synthesized and biologically evaluated as inhibitors of rabbit muscle GPa. Key compound 5 was readily obtained in four steps starting from oleanolic acid (OA; 1). Further modification based on pyrazolo triterpene 5 resulted in 17 novel pyrazolo pentacyclic triterpenes. All of the synthesized pyrazolo[4,3-b]oleanane derivatives were biologically assayed against rabbit muscle GPa. Within this series of compounds, pyrazole triterpene 19 (IC(50)=9.9 microM) exhibited more potent activity than the parent compound 1. Preliminary structure-activity relationship analysis of the pyrazolo[4,3-b]oleanane derivatives as GPa inhibitors is discussed.     

Solid-phase Parallel Synthesis of 4-β-D-Ribofuranosylpyrazolo[4,3-d]pyrimidine Nucleosides

The synthesis of pyrazolo[4,3-d]pyrimidine nucleoside library using solid-phase parallel synthesis methodology is described. Glycosylation of the trimethylsilyl (TMS) derivative of 1- and 2-(methyl)-1H and 2H-pyrazolo[4,3-d]pyrimidine-5,7-(4H,6H)-dione (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of TMS triflate provided two novel protected nucleosides 6 and 7. The structures of 6 and 7 were assigned by 1H and 2D NMR experiments. Nucleosides 6 and 7 were then transformed to the key intermediates 12 and 15 respectively. Reaction of 12 and 15 with MMTCl resin in the presence of 2,6-lutidine afforded the necessary scaffolds B and C. Different amines (96) were introduced selectively by nucleophilic substitution on scaffolds B and C using solid-phase parallel semi-automated synthesizer. Cleavage of the products from the solid support with 30% HFIP in a parallel fashion yielded nucleoside libraries simultaneously, and they were analyzed and characterized by high-throughput LC-MS.     

Potent and selective adenosine A(2A) receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones

Antagonism of the adenosine A_2A receptor affords a possible treatment of Parkinson’s disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A_2A antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A₁) A_2A antagonist activity. Structure-activity relationships are described for this series.     

Design, synthesis and anticancer activity of novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives

On the basis of the chemical structures of psorospermin with a xanthone template and acronycine derivatives with an acridone template, rac-1 and rac-2 constructed on an 1,2-dihydrobenzofuro[4,5-b][1,8]naphthyridin-6(11H)-one scaffold were designed and synthesized as potential anticancer agents. Their anticancer activities were evaluated against five human cancer cell lines. Rac-2 showed similar anticancer activity to doxorubicin and rac-1 exhibited even higher anticancer activity against LNCaP (IC(50)=0.14 μM), DU145 (IC(50)=0.15 μM), PC3 (IC(50)=0.30 μM) and MCF-7 (IC(50)=0.26 μM) cancer lines than doxorubicin and rac-2. Also, rac-1 revealed very potent anticancer activity (IC(50)=0.15 μM) against MCF-7/ADR cell (doxorubicin-resistant breast cancer cell) lines and induced G2/M phase arrest of the cell cycle in MCF-7/ADR cells.     

2-Arylimidazo[2,1-b]benzothiazoles: a new family of amyloid binding agents with potential for PET and SPECT imaging of Alzheimer's brain

We designed and synthesized a small series of 2-aryl-imidazo[2,1-b]benzothiazole, representing a combination of motifs from the two most potent amyloid imaging agents, PIB and IMPY. The binding affinity of the new compounds ranged from 6 to 133 nM. Among the best compounds, 3b (K_i = 6 nM) can be labeled with ¹¹CH₃ for PET imaging whereas 3j (K_i = 10.9 nM) can be labeled with ¹²³I for SPECT imaging.     

Platinum(II) imidazo[4,5-f]-1,10-phenanthroline chloride and thiolate complexes: Synthesis and crystal structures

The planar aromatic imidazo[4,5-f]-1,10-phenanthroline ligands have been used to prepare platinum(II) chloride and thiolate complexes. The X-ray structures of two thiolate compounds are reported, which show column-like packing in the solid state due to intermolecular aromatic π-π interactions. The compounds absorb moderately in the visible region, owing to {charge-transfer-to-diimine} electronic transition.     

Liver Injury Due to 3-Amino-1-methyl-5H-pyrido [4,3-b] indole (Trp-P-2) and Its Prevention by Miso

Trp-P-2(3-amino-1-methyl-5H-pyrido [4,3-b] indole) ingestion for 42 d by C3H/HeJJcl mice caused elevation of serum alanine transaminase (ALT) activity and several signs of liver injury. These alterations were not observed in mice fed the diet supplemented with 10% miso. This suggests a preventive effect of miso as to Trp-P-2 induced liver injury.     

Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold

Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A_2A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for ¹⁸F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, K_i 15 nM). The potent and A_2AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A_2AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A_2AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A_2AAR.     

Novel acenaphtho[1,2-b]pyrrole-carboxylic acid family: Synthesis, cytotoxicity, DNA-binding and cell cycle evaluation

A family of 8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid derivatives were synthesized as a result of our efforts to modify a series of acenaphthopyrrole aromatic-heterocycle compounds that proved to be potent anticancer drugs. Among the derivatives, 3d (3-(dimethylamino-propylamino)-8-oxo-8H-acenaphtho-[1,2-b]pyrrole-9-carboxylic acid) and 3g (3-piperidine-8-oxo-8H-acenaphtho-[1,2-b]pyrrole-9-carboxylic acid) showed potential anticancer activity and different action mechanism from our previously reported compounds. UV–vis absorption, circular dichroism and viscosity measurement indicated that effect of both compounds on the advanced DNA conformation was different, although they could bind to DNA in the same way. Cell cycle analysis showed that 3d could induce S-phase arrest followed by apoptosis, while 3g induced apoptosis. The results seem to imply that different action mechanism could contribute to the dissimilitude of biological activities toward 3d and 3g.