Pyridone Analogues Research Articles

Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

Ru(II) catalyzed chelation assisted C(sp2)-H bond functionalization along with concomitant (4 + 2) annulation.

Efficacious protocols have been established to synthesize a structurally privileged Π-extended coumarin-fused pyridone nucleus by activating the vinylic C(sp2)-H bond of coumarin-3-carboxamide under the influence of inexpensive Ru(II)-metal. Here an N-methoxy carboxamide entity has been exploited as the chelating fragment to manifest C(sp2)-H bond functionalization with a concomitant (4 + 2) annulation reaction, resulting in heterocyclic ring-forming protocols along with sulfoxonium ylide and iodonium ylide as representative bench-stable carbene surrogates. This diverse heterocycle formation via carbene insertion strategies, is further expanded to activate the ortho-C(sp2)-H bonds of different heterocycles by employing the sp2-N moiety as the directing group to develop acyl-alkylated/alkenylated quinazolines, isoxazoles and highly fluorescent pyridone-N-oxides. Intriguingly, during an evaluation of the versatility of the current protocols, a one-pot double C-H activation has been rationalized in the presence of iodonium ylide, which results in biologically potent benzimidazole-fused coumarin-centered bridge-headed polycyclic heteroarenes. Furthermore, a chemo-selective late-stage synthetic transformation is being designed to develop differently substituted pyridone analogues by switching the nature of the reducing agent. In addition, a photophysical experiment was done on one pyridine-N-oxide compound (7e) and delightfully it exhibited fluorescence quenching activity selectively in the presence of Al3+ ions, which appears to be a unique feature of our methodology. Finally, upon correlation of the merit of the developed pathways, the iodonium ylide mediated strategy appears to be superior.

Synthesis, biological evaluation and molecular docking of new triphenylamine-linked pyridine, thiazole and pyrazole analogues as anticancer agents

A new series of pyridine, thiazole, and pyrazole analogues were synthesized. The pyridone analogues 4a-e were synthesized by treating N-aryl-2-cyano-3-(4-(diphenylamino)phenyl)acrylamides 3a-e with malononitrile. Many 4-arylidene-thiazolidin-5-one analogues 6a-d were obtained by Knoevenagel reactions of 4-(diphenylamino)benzaldehyde (1) with their corresponding thiazolidin-5-one derivatives 5a-d. The structural elucidation of the products was proven by the collections of spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Their anti-cancer activity was examined against two cell lines, MDA-MB-231 (mammary carcinomas) and A-549 (lung cancer). Compared with cisplatin as a reference standard drug, 6-amino-4-(4-(diphenylamino)phenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (4b) and 6-amino-4-(4-(diphenylamino)phenyl)-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4e) exhibited better efficiency against the A-549 cell line, with IC50 = 0.00803 and 0.0095 μM, respectively. Also, these compounds 4b and 4e showed the most potency among the examined compounds against MDA-MB-231 with IC50 = 0.0103 and 0.0147 μM, respectively. The newly synthesized compounds were docked inside the active sites of the selected proteins and were found to demonstrate proper binding. 2-Cyano-2-(4,4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)-N-(p-tolyl)acetamide (6c) offered the highest binding affinity (− 8.1868 kcal/mol) when docked into (PDB ID:2ITO), in addition to 2-cyano-N-(4-(diethylamino)phenyl)-2-(4-(4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)acetamide (6a) gave the highest energy score (− 9.3507 kcal/mol) with (PDB ID:2A4L).

Antitumor potential of tricyclic pyridone analogues from an entomopathogenic fungus, Fusarium avenaceum SYKC02-P-1

Two new tricyclic pyridone analogues, fusapyridons C (1) and D (2), were isolated along with structurally related known compounds 3 − 5 from the entomopathogenic fungus, F. avenaceum SYKC02-P-1. The structures of compounds 1 and 2 were elucidated by analyzing the spectral data of UV, 1 D and 2 D NMR as well as HRESIMS. The absolute configurations of fusapyridons C and D were established by means of single crystal X-ray diffraction and electronic circular dichroism calculation. And antitumor testing of all the isolates showed that compounds 4 and 5 exhibited significant inhibitory activity against the human prostate cancer cells (PC-3 cell lines) with IC50 values of 2.76 and 1.86 μM, respectively.

A series of new polycyclic carbamoyl pyridone analogues were synthesized by using chloroacetaldehyde as a substrate

A facile, universal and economical method was developed for the synthesis of polycyclic carbamyl pyridone analogues of Baloxavir marboxil from the cyclization of chloroacetaldehyde with o- aminoamide derivatives. In this method, without any other catalysts or additives, the polycyclic carbamoyl pyridone analogues can be obtained by ring closure of o -aminoamide derivatives and chloroacetaldehyde under the action of a base, and no harsh reaction conditions are required. The method operation is simple and suitable for industrial production. A series of polycyclic carbamyl pyridone analogues were prepared in moderate to excellent yields.

<I>In vitro</I> evaluation of the inhibitory effect of 3, 5-dichloro-2- pyridone on <I>Mycobacterium tuberculosis</I> H37Rv

Purpose: To investigate the anti-tuberculosis potential of twelve commercially available pyridone analogues against Mycobacterium tuberculosis H37Rv strain.Methods: Twelve commercially available pyridone-based compounds were screened against M. tuberculosis H37Rv using different susceptibility tests. The most active or lead compound was further evaluated in detail for its anti-tuberculosis (anti-TB) potential. Kill kinetics was used to determine the dynamics of its anti-TB activity in vitro.Results: Compounds d, j and k were potent against M. tuberculosis H37Rv, with minimum inhibitory concentrations (MICs) of 10, 5 and 10 μg/mL, respectively. The standard anti-TB drugs used in this study (positive control drugs) demonstrated MIC of 2.5 μg/mL. The anti-TB effect of compound j was comparable with those of the standard drugs (RIF, LVX, AMK, EMB and INH). The minimum bactericidal concentration (MBC) of compound j was 10 μg/mL. It produced an MIC of 5 μg/mL in agar proportion method (APM). However, its MIC in Middlebrook 7H9 broth supplemented with 10 % fetal bovine serum (FBS) and 4 % bovine serum albumin (BSA) increased 4- and 8-fold, respectively. The bactericidal effect of compound j was time- and concentration-dependent at dilutions above 2x MIC. Combination of compound j with RIF, LVX or AMK exhibited fractional inhibitory concentration index (ΣFIC) of 1, indicative of additive drug-drug interactions. However, combination with INH or EMB produced a ΣFIC of 2. None of the tested drug combinations was antagonistic.Conclusion: Compound j exhibits potent time- and concentration-dependent antimicrobial effect against M. tuberculosis H37Rv. Thus, it may be suitable as an adjunct to current treatment of drug sensitive and drug-resistant TB.
 Keywords: Tuberculosis, Mycobacterium tuberculosis, Pyridone analogs, Antimicrobial activity, Antibiotics

Pyridone Luciferins and Mutant Luciferases for Bioluminescence Imaging.

New applications for bioluminescence imaging require an expanded set of luciferase enzymes and luciferin substrates. Here, we report two novel luciferins for use in vitro and in cells. These molecules comprise regioisomeric pyridone cores that can be accessed from a common synthetic route. The analogues exhibited unique emission spectra with firefly luciferase, although photon intensities remained weak. Enhanced light outputs were achieved by using mutant luciferase enzymes. One of the luciferin-luciferase pairs produced light on par with native probes in live cells. The pyridone analogues and complementary luciferases add to a growing set of designer probes for bioluminescence imaging.

Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy

Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90μM in NIH3T3 cell lines, t1/2 of 4.89±1.33h in male rats and LD50>2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.

Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of α-l-fucosidase

Hydantoin, thiohydantoin and pyridone analogs as α-l-fucosidase inhibitors through bioisosteric modification of known bovine α-l-fucosidase inhibitors.

QSAR and Molecular Modeling Studies on a Series of Indole-based Pyridone Analogues as HCV NS5B Polymerase Inhibitors

Quantitative structure-activity relationship (QSAR) and molecular modeling studies have been performed on a series of indole-based pyridone analogues as hepatitis C virus (HCV) NS5B polymerase inhibitors. A multiple linear regression (MLR) analysis has shown that the presence of hydrogen- bond donors in the molecule plays a negative role, but the substituents present on the indole ring sterically favor the activity of indole-based pyridine analogues. Using the MLR analysis model, some new analogues of indole-based pyridone with better potency have been predicted. Docking study has been performed on all the predicted compounds to study their binding modes with the receptor. Keywords: Indole-based pyridone analogues, Hepatitis C virus inhibitors, NS5B polymerase inhibitors, Quantitative structureactivity relationships, Molecular docking.

Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.

Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles

This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.

Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists

6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.

Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.

ChemInform Abstract: Synthesis of Bicyclic Pyridone and Dihydropyridone Analogues of β- Lactam Antibiotics.

Condensation of the vinylogous urethanes 2, 26, 28 and 29 with acrylates, haloacrylates and propiolic acid has afforded easy access to bicyclic dihydropyridone and pyridone analogues of cephalosporins, carbapenams, penicillins and bisnorpenicillins. Synthesis of the pyridone is accompanied, in one instance, by an interesting cyclisation to the glutaconic anhydride 23 and significant differences in tautomeric behaviour have been found between the five-membered vinylogous urethanes 28 and 29 and their six-membered counterparts 2.

ChemInform Abstract: A Facile and Efficient Method for the Synthesis of Novel Pyridone Analogues by Aminolysis of an Ester under Solvent‐Free Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A facile and efficient method for the synthesis of novel pyridone analogues by aminolysis of an ester under solvent-free conditions

A series of 15 pure novel N-alkylated pyridone derivatives have been synthesized in 73–96% yields on treatment of ethyl (2-pyridone)acetates with structurally diverse amines in an efficient aminolysis procedure under ‘solvent-free’ conditions.

Synthesis of new optically active bis-pyridino- and bis pyridono-18-crown-6 type ligands containing four lipophilic chains attached to the chiral centers by "two-to-two" type macrocyclization

Three new optically active bis-pyridino-18-crown-6 type ligands containing four lipophilic chains at the chiral centers [(S,S,S,S)-10, (R,R,R,R)-11 and (S,S,S,S)-12] were prepared by sodium ion template effect assisted “two-to-two” type macrocyclizations. The benzyloxysubstituted (R,R,R,R)-11 and (S,S,S,S)-12 were transformed to the new pyridone analogues (R,R,R,R)-13 and (S,S,S,S)-14 by catalytic hydrogenation.

Novel Generation of PyridiniumYlides fromN-(Silylmethyl)pyridone Analogs via1,4-Silatropy and their 1,3-Dipolar Cycloadditions Leading toN-Heteropolycycles

Non-stabilized pyridinium methylides were successfully generated from N-(siliymethyl)pyridone analogs via 1,4-silatropy and the resulting 1,3-dipoles were trapped by reaction with acetylenic and olefinic dipolarophiles to afford N-heteropolycycles. The method does not require the use of any additives or strong bases.

Synthesis of bicyclic pyridone and dihydropyridone analogues of β-lactam antibiotics

Condensation of the vinylogous urethanes 2, 26, 28 and 29 with acrylates, haloacrylates and propiolic acid has afforded easy access to bicyclic dihydropyridone and pyridone analogues of cephalosporins, carbapenams, penicillins and bisnorpenicillins. Synthesis of the pyridone is accompanied, in one instance, by an interesting cyclisation to the glutaconic anhydride 23 and significant differences in tautomeric behaviour have been found between the five-membered vinylogous urethanes 28 and 29 and their six-membered counterparts 2.