Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles.

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.     

Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.     

Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives

Synthesis and primary SAR of a novel series of 2-phenylpyrido[1,2-e]purin-4(3H)-one derivatives with piperazinyl sulfonamide substituents were described herein. As potential PDE5 inhibitors for erectile dysfunction (ED) treatment, representative compounds exhibit improved selectivity versus PDE1 and PDE6. Meanwhile, compound 3e demonstrated functional efficacy on rabbit corpus cavernosum strip in vitro.     

Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents

4-Substituted-pyrido[2,3-d]pyrimidin-4(1H)-ones 4a–c were synthesized by oxidation of 4-substituted-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 3a–c which were in turn prepared from arylidenemalononitriles 1a–c and 6-aminothiouracil 2. The reactivity of compounds 4a–c towards some reagents such as formamide, carbon disulfide, urea, thiourea, formic and acetic acids were studied. All the synthesized compounds were characterized by spectroscopic means and elemental analysis. Compound 4c exhibited 64% and 72% analgesic activity. Also, compound 4b showed 50% and 65% anti-inflammatory activity. Interestingly these compounds showed one-third of ulcer index of the reference aspirin and diclofenac.     

IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines

Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.     

Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrrolo[1,2-a]quinoxalines as antileishmanial agents

An original series of 4-substituted pyrrolo[1,2-a]quinoxaline derivatives, new structural analogues of Galipea species quinoline alkaloids, was synthesized from various substituted 2-nitroanilines via multistep heterocyclizations and tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Structure-activity relationships enlighten the importance of the 4-substituted alkenyl side chain on the pyrrolo[1,2-a]quinoxaline moiety to modulate the antileishmanial activity.     

Synthesis, X-ray crystal structure and optical properties of novel 2-aryl-3-ethoxycarbonyl-4-phenylpyrido[1,2-a]benzimidazoles

A series of novel 2‐aryl‐3‐ethoxycarbonyl‐4‐phenylpyrido[1,2‐a]benzimidazole derivatives were synthesized by the tandem reaction of 2‐benzoyl benzimidazole and (Z)‐ethyl 4‐bromo‐3‐arylbut‐2‐enoate in the presence of potassium carbonate. The compounds were characterized using IR, ¹H‐NMR, ¹³C‐NMR, HRMS and the structure of 6f was further determined by X‐ray crystallography. Both absorption and fluorescence spectra characteristics of the compounds were investigated in acetonitrile and dichloromethane. The results showed that the absorption maxima of the compounds varied from 220 to 284 nm, depending on the structure of 2‐aryl group. The fluorescence results revealed that these compounds exhibited blue‐green fluorescence (463–475 nm) in dilute solutions and showed acceptable fluorescence quantum yields (Ф_PL = 0.13–0.73) in dichloromethane. Copyright © 2011 John Wiley & Sons, Ltd.     

Pyrazino[1,2-a]indoles as novel high-affinity and selective imidazoline I(2) receptor ligands

1,2,3,4-Tetrahydropyrazino[1,2-a]indoles are described as a novel class of I(2) imidazoline receptor ligands. In particular, 8-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indole (8-OMe THPI; 3c) binds with high affinity at I(2) imidazoline receptors (K(i)=6.2 nM) and with exceptional (> or =1000-fold) selectivity relative to its affinity for I(1) imidazoline receptors, alpha(2)adrenergic receptors, and 5-HT(2A) and 5-HT(2C) serotonin receptors.     

IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding

A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.     

Pyrrolo[1,2-a][1,4]benzodiazepine: a novel class of non-azole anti-dermatophyte anti-fungal agents

Broad screening revealed compound 1a to be a novel anti-fungal agent with high specificity towards dermatophytes. The anti-fungal structure-activity relationship of this novel class of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines is described together with its mode of action that appeared to be the inhibition of squalene epoxidase. Preliminary in vivo results of the most active compounds are also reported.     

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.     

Axial chirality and affinity at the GABA(A) receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2'-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABA(A) receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC(50) value of 1.5 nM.     

Synthesis of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions

A series of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives, structural analogues of alkaloid chimanine B, was synthesized in good yields using efficient palladium(0)-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Biological results showed activity against the promastigote forms of L. amazonensis and L. infantum with IC₅₀ ranging from 0.5 to 7 μM. From a Structure-Activity Relationships point of view, these pharmacological results mainly enlightened the importance of the 4-lateral C₆, C₇ or C₈ α-unsaturated trans-alkenyl chain of unsubstituted pyrrolo[1,2-a]quinoxaline moiety.     

Synthesis of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions

A series of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives, structural analogues of alkaloid chimanine B, was synthesized in good yields using efficient palladium(0)-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Biological results showed activity against the promastigote forms of L. amazonensis and L. infantum with IC50 ranging from 0.5 to 7 microM. From a Structure-Activity Relationships point of view, these pharmacological results mainly enlightened the importance of the 4-lateral C6, C7 or C8 alpha-unsaturated trans-alkenyl chain of unsubstituted pyrrolo[1,2-a]quinoxaline moiety.     

Research of imidazo[1,2-a]benzimidazole derivatives. XXX. Synthesis and properties of (imidazo[1,2-a]benzimidazolyl-2)acetic acid derivatives

Ethyl esters of (9-subtituted-imidazo[1,2-a]benzimidazolyl-2)acetic acids were synthesized. The chemical properties of these esters (hydrolysis, decarboxylation, hydrazinolysis) and biological activity (fungicidal, antimicrobial, antiarrhythmic activity, and also affects on the brain rhythmogenesis) of the prepared compounds were studied.     

Imidazo[1,2-a]pyrazine diaryl ureas: Inhibitors of the receptor tyrosine kinase EphB4

Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent^® and Nexavar^®, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.     

Synthesis of new 4-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives la-1 is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2- a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue la, opening the way to further pharmacomodulation.     

Potential antidiabetic activity and molecular docking studies of novel synthesized 3.6-dimethyl-5-oxo-pyrido[3,4-f][1,2,4]triazepino[2,3-a]benzimidazole and 10-amino-2-methyl-4-oxo pyrimido[1,2-a]benzimidazole derivatives

Diabetes affects a large population of the globe and is considered as a leading cause of death. Many synthetic and natural inhibitors have been developed for diabetes treatment. Herein, we report the potential antidiabetic activity of two new heterocyclic systems, namely 3.6-dimethyl-5-oxo-pyrido[3,4f][1,2,4]triazepino[2,3-a]benzimidazole (I) and 10-amino-2-methyl-4-oxo pyrimido[1,2-a]benzimidazole (II) against three related enzymes: α-amylase, α-glucosidase and β-galactosidase. Compounds I and II were synthesized by the action of DMF-DMA and dimethyl sulfate in the presence of water on 2-methyl-3H-benzimidazolo[1,2b][1,2,4]triazepin-4(5H)-one, and are characterized by single X-ray diffraction. The binding interaction modes in the active sites of I and II and targeted enzymes (stable complexes ligand-receptor) are emphasized using the molecular docking approach by applying the Lamarckian genetic algorithm method. Furthermore, plausible mechanisms have been proposed explaining their synthesis. Hirshfeld surface analysis reveals the nature of molecular interactions and fingerprint plots provide information about the percentage contribution from each individual molecular contact to the structure surface.

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Graphical abstract Left Molecular packing of 1,4-dimethyl-2-oxo-pyrimido[1,2-a]benzimidazole hydrate. Right Docking active site of α-glucosidase

     

Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives,as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives 1a-l is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue 1a, opening the way to further pharmacomodulation.     

Synthesis and SAR of 2-(4-fluorophenyl)-3-pyrimidin-4-ylimidazo[1,2-a]pyridine derivatives as anticoccidial agents

Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.