Imidazo[4,5-b]pyridine derivatives of potential tuberculostatic activity, II: Synthesis and bioactivity of designed and some other 2-cyanomethylimidazo[4,5-b]pyridine derivatives.

Based on the analysis of Quantitative Structure--Activity Relationships (QSAR) three representatives of imidazo[4,5-b]pyridine derivatives of predicted high antibacterial activity against Mycobacterium tuberculosis were synthetized and tested bacteriologically. Excellent agreement of the predicted and experimentally observed bioactivity was noted. Additional new derivatives of 4-methyl-4H-2-cyanomethylimidazo[4,5-b]pyridine (7) and 2-(alpha-methylcyanomethyl)imidazo[4,5-b]pyridine (22) were also synthesized and some of them were tested for tuberculostatic activity. The compounds synthesized according to a standard "trial and error" approach appeared generally inactive.     

Synthesis and pharmacological properties of some derivatives of 3-phenylimidazo[4,5-b]pyridine

The one-pot synthesis and properties of some derivatives of 3-phenylimidazo [4,5-b]pyridine (4a-g) were described. The central action of compounds 4a, 4f and 4g has been investigated using behavioral tests in mice and rats. The tested compounds showed a potent sedative effect. Compound 4f has central serotoninolytic properties in the m-CPP induced hyperthermia in rats.     

Synthesis and tuberculostatic activity of some derivatives of imidazo [4, 5-b]pyridine-1-carboxylic acid

Imidazo [4,5-b] pyridine-2-carboxylic acid 2, its methyl ester 5, amide 7, hydrazide 12, hydrazone 14, nitrile 16, thioamide 18, and amidoxime 20 were synthesized. By methylation of acid 2 with diazomethane N3-CH3 derivatives of the above mentioned compounds were obtained. The resulting compounds displayed low tuberculostatic activity.     

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11). The structures of 4-6 and 8-10 were identified by the results of elemental analysis and their IR, 1H-NMR and MS spectra. Additionally, the structure of 11 was confirmed by X-ray diffraction method. Compounds 8-10 and 11 were examined for their antiproliferative activity in vitro against the cells of 5 human cancer cell lines, using SRB or MTT technique. Among tested compounds, only 11 revealed cytotoxic activity in vitro against all cell lines applied with ID50 (inhibitory dose 50%) values lower than 4 microg/mL, which is an international activity criterion for synthetic compounds. All compounds inhibit the proliferation of HL-60 human promyelocytic leukemia cell line.     

Pharmacological activity of 2-mercaptopyrimido[4,5-b]indole and 2-mercapto-3-formylindole derivatives

The pharmacological properties of two compounds with new heterocyclic structures, pyrimido[4,5-b]indole and 2-mercapto-3-formylindole, were synthesized and studied on the models of hypobaric hypoxia, toxic pulmonary edema, and acute toxic liver injury. Both chemical structures showed a combination of antihypoxant and antiinflammatory activity. In addition, 2-mercapto-3-formylindole derivatives exhibited a significant hepatoprotective effect. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 5, pp. 17–19, May, 2006.     

2,3-Diaryl-3H-imidazo[4,5-b]pyridine derivatives as potential anticancer and anti-inflammatory agents

In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC₅₀ values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.     

Synthesis and some reactions of 2-acetylimidazo[4,5-b]pyridine. Antituberculotic activity of the obtained compounds.

2-Acetylimidazo[4,5-b]pyridine was prepared and its reactions with some aromatic amines and sulfur (Willgerodt-Kindler reaction), some aromatic aldehydes, some carboxylic acid hydrazides as well as thiourea were investigated. New imidazo[4,5-b]pyridine derivatives with different substituents in 2-position (N-arylthioamides, imines, alpha, beta-unsaturated ketones, hydrazido-hydrazones and aminothiazole) were obtained. Most of the synthesized compounds were tested in vitro for their antituberculotic activity.     

2-[3-(1,1-Dimethylethyl)-5-methoxyphenyloxazolo[4,5-b]pyridine, a new topical antiinflammatory and analgesic compound lacking systemic activity and gastric side effects

The substituted oxazolopyridine 2-[3-(1,1-dimethylethyl)-5-methoxyphenyl]oxazolo[4,5-b]pyridine (OZP) inhibits phorbol myristate acetate-induced increases in vascular permeability and neutrophil accumulation in rat ears with ED50 of 253 and 200 micrograms, respectively. This compound is as potent as indomethacin to inhibit UV-induced erythema in guinea pig skin and is an effective analgesic when applied topically to the rat footpad in the yeast hyperalgesia model. OZP is a cyclooxygenase inhibitor with an IC50 of 0.06 mumol/l and inhibits prostaglandin E2, but not leukotriene C4 synthesis, by mouse peritoneal macrophages. This compound is inactive in the carrageenan paw edema assay at 90 mg/kg when administered orally or intraperitoneally, but is effective when injected into the paw. OZP is not a contact allergen and does not cause gastric irritation in rats at doses up to 180 mg/kg orally. OZP is rapidly metabolized by rat liver microsomes in a concentration and time dependent manner. Furthermore, when administered orally, OZP is cleared rapidly in rats with plasma levels being detected only at 5 and 30 min following a 2 mg/kg dose. There was no drug in the gastrointestinal tract of rats 3 h after an oral dose. Thus, this compound appears to be a new, potent and safe topical antiinflammatory and an analgesic agent lacking systemic effects.     

BYK191023 (2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3h-imidazo[4,5-b]pyridine) is an NADPH- and time-dependent irreversible inhibitor of inducible nitric-oxide synthase

Imidazopyridine derivates were recently shown to be a novel class of selective and arginine-competitive inhibitors of inducible nitric-oxide synthase (iNOS), and 2-[2-(4-methoxypyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) was found to have very high selectivity in enzymatic and cellular models ( Mol Pharmacol 69: 328-337, 2006 ). Here, we show that BYK191023 irreversibly inactivates murine iNOS in an NADPH- and time-dependent manner, whereas it acts only as a reversible l-arginine-competitive inhibitor in the absence of NADPH or during anaerobic preincubation. Time-dependent irreversible inhibition by BYK191023 could also be demonstrated in intact cells using the RAW macrophage or iNOS-overexpressing human embryonic kidney 293 cell lines. The mechanism of BYK191023 inhibition in the presence of NADPH was studied using spectral, kinetic, chromatographic, and radioligand binding methods. BYK191023-bound iNOS was spectrally indistinguishable from l-arginine-bound iNOS, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. [(3)H]BYK191023 was recovered quantitatively from irreversibly inactivated iNOS, and no inhibitor metabolite was detected by high-performance liquid chromatography (HPLC). Size exclusion chromatography revealed only about 20% iNOS dissociation into monomers. Furthermore, HPLC and spectrophotometric analysis showed that the irreversible inhibition was associated with loss of heme from iNOS and a reduced ability to form the distinctive ferrous heme-CO complex (cytochrome P450). Thus, enzyme inactivation is mainly caused by heme loss, and it occurs in the inhibitor-bound enzyme in the presence of electron flux from NADPH.     

Novel antiinflammatory analgesics: 3-(2-/4-pyridylethyl)-benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives

Twenty-two new 3-[2-(2-and/or 4-pyridyl)ethyl]benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives have been synthesized by reacting 2- and/or 4-vinylpyridine and appropriate benzoxazolinones and oxazolo[4,5-b]pyridine-2-one. Their chemical structures have been proven by IR. 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis. The analgesic activities of these compounds were investigated by a modified Koster's Test. Test results revealed that, at 100 mg/kg dose level, most of the compounds showed significant analgesic activities when compared to aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. Compounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 21 were found more active than indomethacine. In gastric ulceration studies gastrointestinal bleeding was not observed at 100 mg/kg dose level in compounds 1 and 2.     

2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)- phenylcarbamoylsulfanyl]propionic acid and its derivatives as a novel class of glutathione reductase inhibitors

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione to reduced glutathione. The enzyme is an attractive target for the development of antimalarial agents, agents to decrease malarial drug resistance and anticancer agents. In addition, inhibition of the enzyme has been employed as a tool in research for various purposes. In this paper, we present a rational design of 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyl]propionic acid and its derivatives as irreversible GR inhibitors. The K(i) and k(inact) values of 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenylcarbamoylsulfanyl]propionic acid, the most potent derivative of the series, are 88 muM and 0.1 min(-1), respectively. Although the K(i) value of the inhibitor is in the micromolar range, it is more potent than N,N-bis(2-chloroethyl)-N-nitrosourea, which is currently the most commonly employed irreversible GR inhibitor with a reported IC(50) value of 646 microM. Additional attractive features of the inhibitor include its ready availability through a one-step synthesis and good solubility in both organic and aqueous solutions.     

Synthesis and some reactions of 2-cyanomethylimidazo [4,5-b]pyridine. Tuberculostatic investigations of obtained compounds

2-Cyanomethylimidazo [4,5-b]pyridine 1 was obtained and its properties during acid and basic hydrolysis, esterification, and reaction with hydrogen sulfide were investigated. Condensation of 1 with aromatic aldehydes was also studied. Some of the obtained compounds were tested on tuberculostatic activity.