INTRODUCTION:
Chemistry
Pyridine is a simple aromatic heterocyclic organic compound with the chemical formula C5H5N used as a precursor to agrochemicals and pharmaceuticals and is also an important solvent and reagent. It is structurally related to benzene where in one CH group in the aromatic six-membered ring is replaced by a nitrogen atom. It exists as a colorless liquid with a distinctive unpleasant fish-like odour. The pyridine ring occurs in many important compounds including nicotinamides.
Pyridine was originally industrially produced by extraction from coal tar. It is currently synthesized from formaldehyde, ammonia and acetaldehyde:
CH2O + NH3 + 2 CH3CHO → C5H5N + 3 H2O + H2
For specialized applications the synthesis of the pyridine skeleton is well developed. The Hantzsch pyridine synthesis for example is a multicomponent reaction involving formaldehyde a keto-ester and a nitrogen donor.
The Kröhnke pyridine synthesis involves the condensation of 1,5-diketones with ammonium acetate in acetic acid followed by oxidation. The Ciamician-Dennstedt Rearrangement entails the ring-expansion of pyrrole with dichlorocarbene to 3-chloropyridine. In the Gattermann-Skita synthesis a malonate ester salt reacts with dichloromethylamine.
Pyridine is an important solvent and reagent in organic synthesis. It is used as a solvent in Knoevenagel condensations. It is the precursor to myriad insecticides, herbicides, pharmaceuticals, food flavorings, dyes, rubber chemicals, adhesives, paints, explosives and disinfectants.
Pyridine is a widely used polar but aprotic solvent. It is miscible with a broad range of solvents including hexane and water. Deuterated pyridine called pyridine-d, is a common solvent for1H NMR spectroscopy.
BIOLOGICAL ACTIVITIES:
Anticonvulsant activity
A series of N’-[substituted] pyridine-4-carbohydrazides were designed and synthesized by Tripathi et al1 and evaluated for anticonvulsant activity and neurotoxicity after intraperitoneal administration in three seizure models which include MES, scMET and 6 Hz model. N’-[4-(4-fluorophenoxy) benzylidene]pyridine-4-carbohydrazide (1) was found to be most active compound which showed a MES ED50 value of 128.3 mg/kg and 6 Hz ED50 value of 53.3 mg/kg in mice. The median toxic dose (TD50) was 343.6 mg/kg with a protection index of 2.67 in the MES test and 6.44 in 6 Hz test
Following a design methodology including pharmacophoric requirements and ADME-predicted properties Falco et al2 have synthesized a library of 3-amino-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones (2) and their N1-alkyl derivatives as new scaffolds for designing non-benzodiazepine BZ receptor ligands.
In vivo receptor occupancy of mGlu5 receptor antagonists was quantified by Anderson et al3 in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy) (3). Administration of [3H]methoxy-PEPy (50 μCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrated that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.
Structure-activity relationship studies performed around 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile by Poon et al4 for the purpose of developing novel mGlu5 receptor antagonists are described. Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine (4), a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist.
Tehrani et al5 performed the structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (5) which led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile was found to be highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration and in vivo receptor occupancy.
Huang et al6 carried out structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile that led to the discovery of 2-{2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl}pyridine (6), a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability.
Mitchinson et al7 developed 2,5-dihydropyrazolo[4,3-c]pyridin-3-ones (7) that were GABAA receptor benzodiazepine binding site ligands with functional selectivity for the α3 sub type over the α1 sub type. SAR studies to optimize this functional selectivity were described.
Borowicz et al8 worked on 2-Methyl-6-phenylethynyl-pyridine (8, MPEP) a selective noncompetitive mGluR5 antagonist that influences the action of conventional antiepileptic drugs in amygdala-kindled seizures in rats. MPEP alone (up to 40 mg/kg) did not affect any seizure parameter. Moreover, the common treatment of MPEP with either carbamazepine or phenytoin (administered at sub effective doses) did not result in any anticonvulsant action in kindled rats. However, when combined with sub protective doses of valproate or phenobarbital, MPEP significantly shortened seizure and after discharge durations. Importantly combinations of MPEP with the two antiepileptics did not have the adverse effects of impaired motor performance or long-term memory in rats. The data indicated that MPEP may positively interact with some conventional antiepileptic drugs in the amygdala-kindling model of complex partial seizures.
Subudhi et al9 reported a series of 3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(substituted)pyridines (9) that were synthesized by Hantzsch method for pyridine synthesis. Treatment with chloroacetyl chloride produced N-(2-chloroacetyl)-3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(substituted) pyridines which on further treatment with sulfanilamide resulted in 3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6-dimethyl-N-[2-(4-sulfamoylphenylamino)-acetyl]-4-(substituted)pyridines. The structures had been established on the basis of spectral (IR, 1H-NMR, mass) and elemental analysis. Compounds (5 mg/kg and 10 mg/kg) were evaluated for their anticonvulsant effect against pentylenetetrazole-induced convulsions with diazepam (4 mg/kg) as the reference. Some compounds exhibited significant (p < 0.01) anticonvulsant activity compared to the control.
A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine (10) in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized by Navidpour et al10 and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle and the activity against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance and the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrated that two compounds were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.
The synthesis and anticonvulsant properties of new 1-(2-pyridinyl)- succinimides (11) differently substituted at the position-3 of imide ring had been described by Kaminiski et al.11 The profile of pharmacological activity of these compounds was examined by a maximal electroshock (MES) and pentylenetetrazole (scPTZ) tests whereas their neurotoxicity was determined using a rotarod screen. The results obtained revealed that the anticonvulsant activity depends mainly on the kind of substituents at the position-3 of pyrrolidine-2,5-dione ring. The most active were 3,3-dialkyl-pyrrolidine-2,5-diones as well as compounds with 3-methylcyclohexane moiety as a spiro nucleus at position-3 of the imide ring. The 3-cyclohexylsuccinimides with cyclohexane ring as a flexible fragment were less active whereas unsubstituated derivatives were devoid of activity in both tests. In addition, the anti-seizure protection depends on the position of methyl group at the pyridine moiety. The most potent compounds were with the methyl substituent at the position-4 or -6. It should be noted that in the whole series the most active was 1-(4-methyl-2-pyridinyl)-3-cyclohexyl-pyrrolidne-2,5-dione, which showed the anti-scPTZ protection at the dose of 30 mg/kg.
A series of 2-substituted-3-arylpyrido[2,3-d]pyrimidinones (12) was prepared by White et al12 for evaluation as potential anticonvulsants. In murine screening, compounds having a 2-oxo-2-(4-pyridyl)ethyl group in the 2-position and a 2-substituted phenyl moiety at the 3-position of the pyridopyrimidinone system displayed the most potent anti-seizure activity in both the maximal electroshock (MES) and pentylenetetrazol (scPTZ) tests at doses in the 3-10 mg/kg range. One compound showed no agonist activity at the GABAA receptor and was unable to block presynaptic sodium and calcium channels in vitro
Antimicrobial activity
Ozdemir et al13 synthesized eight new tetrahydroimidazo[1,2-a]pyridine derivatives and screened for their antifungal effects against a panel of ten human pathogenic Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida utilis, and Candida zeylanoides using agar diffusion and broth microdilution assays, compound 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid-(4-cyanobenzylidene) (13) showed very strong inhibitory activity (up to MIC 0.016 mg/mL) against the screened Candida species.
A series of pyridine amides (14,15) were synthesized by Nakmoto et al14 and tested for in vitro antifungal activity against fungi. Synthesized compounds (14a-d), (15) showed potent antifungal activity against Candida albicans and Aspergillus fumigates having MIC value comparable to the most commonly used antifungal agents Fluconazole and amphotericin B in standard in vitro growth inhibition assay.
A series of 4-Hydroxy-4-(pyridyl)alk-3-en-2-ones (16,17) were synthesized by base-mediated condensation of ketones with pyridinecarboxylates. Several derivatives showed weak antimicrobial activity against Gram-positive and Gram-negative bacteria of which (16a),(16b),(17a) and (17b) were the most active one. Riahi et al15.
Fassihi et al16 synthesized a series of 2-alkyl-3-hydroxy-5-N-piperidylmethyl (18) N,N dialkylaminomethyl pyridine-4-ones(19) and, two derivatives of N-aryl-2- methyl-3-hydroxy-pyridine-4-ones(20) and screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue assay (MABA) method. Synthesized compounds showed a better quantitative structure–activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus.
Starr et al17 synthesized 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine (21), which is found to be dual inhibitors of bacterial gyrB and parE , and exhibited excellent performance against important Gram –possitive pathogens including wild type and methicillin-resistant staphylococcus and wild type and FQR streptococcus and possess desirable in-vivo pharmacokinetic and efficacy properties.
Khalil et al18 carried out glucosidation of some 4-amino- and 4-arylideneamino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thiones with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N- and S-β-d-glucosides (22, 23). The structure of these two regiosiomers was established chemically and spectroscopically. Deamination as well as deacetylation of some selected nucleosides has been achieved. Antimicrobial screening of 14 selected compounds resulted in their activity against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli.
Bondock et al19 used enaminonitrile as key intermediate for the synthesis of poly functionally substituted heterocycles (e.g. pyrazoles, isoxazole, pyrimidines, thiazolo[3,2-a]pyrimidine, tetrazolo[1,5-a]pyrimidine, pyrido[1,2-a]pyrimidine (24), 1,5-benzodiazepine and pyrazolo[1,5-a]pyrimidine) incorporating benzothiazole moiety via its reactions with some N-nucleophiles. The newly synthesized compounds were characterized by IR, 1H NMR and mass spectral studies. Representative compounds of the synthesized products were tested and evaluated as antimicrobial agents.
Desroy et al20 reported that Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) displayed attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represented an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors (25, 26) of HldE kinase. Study of the structure-activity relationship of this series of inhibitors led to highly potent compounds.
Antidiabetic activity
Fifteen novel derivatives of α-amyrin were synthesized by Narender et al 21 and their antihyperglycemic activity profile was assessed by sucrose challenged streptozotocin induced diabetic rat (STZ-S)model. The synthesized compounds i.e. nicotinic acid derivative (27) showed potent antihyperglycemic activity at 100 mg/kg body weight.
Humphries et al22 synthesized a series of novel pyridine-2-propanoic acids and by the study of structure–activity relationship of these compounds led to the identification of potent dual PPARa/c agonists. Compound (S)-(28) appeared to be most potent glucose lowering agents than rosiglitazone based on oral dose in diabetic (db/db) mice.
Ishikawa et al23 synthesized novel 2-(pyridine-2-yl)-1H-benzimidazole. Structural modification of benzimidazole and high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator (29)(R) and this compound demonstrated acute oral glucose lowering efficacy in rat OGTT model.
Bahekar et al24 have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine, N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine and N-(1H-indol-3-yl)-guanidine (30) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion only in presence of glucose load (16.7 mmol). Some of the test compounds from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline) which indicated that the guanidine group acts as a bio-isostearate of imidazoline ring system.
Van Zandt et al25 made the efforts to identify treatments for chronic diabetic complications that had resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid (31) aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50 > 100 μM) a related enzyme involved in the detoxification of reactive aldehydes.
Takamura et al26 reported the synthesis and biological activity of a novel series of oximes and amides having α-substituted-β-phenylpropionic acids (32). In this series they obtained potent PPARα/γ dual agonist with which activation of PPARα and PPARγ were considerably more potent than that of the reference compounds GW9578 and rosiglitazone respectively. It was found to be of the strongest class of PPARα/γ dual agonists. In the course of this study they also obtained a compound which indicated potent plasma glucose lowering effect in spite of weak PPARα/γ agonistic activity.
A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one (33) inhibitors of insulin-like growth factor I (IGF-1R) kinase was described by Wittman et al.27 They discussed the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
Antiviral activity
Chezal et al28 synthesized a series of imidazo[1,2-a]pyrrolo[2,3-c]pyridines (34) and evaluated for their anti-BVDV activities in MDBK cells. From the synthesized different analogues compounds (34a), (34b), (34c), (34d), (34e), and (34f) showed significant anti-BVDV activities.
Schnut et al29 synthesized a series of 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxylate esters (35) which are found to be non-nucleoside inhibitors of human herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases. Compound exibit broad spectrum herpes antiviral activity superior to that of available therapies with respect to HCMV, VZV and EBV.
Hosono et al30 synthesized a series of Histidine–pyridine–histidine (HPH) (36) derivatives and evaluated for their antiviral activities against herpes simplex.
Virus type 1. Compound (36a) showed potent antiviral activity with an EC50 of 15 µM and relatively high cytotoxicity with a CC50 of 37 µM. Compound (36b) showed weak antiviral activity with an EC50 of 79 µM but having less cytotoxicity.
Novel urea primaquine derivatives (37) were synthesized by Dzimbeg et al31 and evaluated for cytostatic and antiviral activity compound (37a) showed best cytostatic activities against colon carcinoma human T-lymphocyte and murine leukemia. Along with some selective inhibition against cyto megalo virus but having marked cytotoxicity towards human normal fibroblasts.
Vrencken et al32 reported that 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP) (38) to be highly potent inhibitor of the in vitro replication of CSFV(classical swine fever virus) thus having the potential to control the spread of infection in an epidemic situation. This compound resulted in a dose-dependent antiviral effect in PK15 cells with a 50% effective concentration (EC50) for the inhibition of CSFV Alfort187 and for CSFV Wingene.
A series of imidazo[1,2-a]pyridines (39) bearing a phenethylthiomethyl side chain at the 3 position with a (hetero) aryl substituent on the 6 or 8 position and evaluated for antiviral activities by veron et al33. Compounds 6-halogeno and 6-phenylimidazo [1,2-a]pyridine derivatives (39a),(39b), and (39c) were the most potent against human cytomegalovirus (CMV) and/ or varicella-zoster virus (VZV).
Gudmundsson et al34 synthesized a series of 2-aryl-3-pyrimidyl-imidazo [1,2-a]pyridines(40) having potent activity against herpes simplex viruses. Several compounds showed in vitro antiviral activity similar or better than acyclovir.
Snoeck et al35 described an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (41, CMV423) that showed very potent in vitro activity against HCMV. CMV423 was highly active against HCMV reference strains and clinical isolates, but also against those strains isolated from patients or emerging after in vitro selection that were resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models that were both highly relevant for the pathophysiology of HCMV the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry as well as time of addition experiments confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and most likely coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.
An efficient synthesis of methyl 7-hydroxy[1,3]thiazolo[5,4-b]pyridin-5(4H)-one-6-carboxylates and 6-carboxamides (42) were described by Boros et al.36 Sub-micromolar enzyme inhibition of HIV integrase was achieved (HIV integrase strand transfer IC50 range = 151–0.03 μM.) with several carboxamide analogs which was superior to their carboxylic ester congeners.
Randolph et al37 developed compounds bearing pyridylmethyl substituents at P3 (43). Potent analogs in this series provided low single-digit nanomolar EC50 values against both wild-type HIV and resistant mutant virus (A17) attenuated some 3- to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5 mg/kg each) in the rat, with average AUC > 8 μg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC < 2 μg h/mL). The 3-pyridylmethyl analog gave the best overall exposure (rat AUC = 7.1 μg h/mL and dog AUC = 4.9 μg h/mL) however, this compound was found to be a potent inhibitor of cytochrome P450 3A (Ki = 2.4 nM).
Anticancer activity
Maria-João et al38 synthesized a several methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine (44) were prepared by Sonogashira coupling and their growth inhibitory effects were evaluated in three representative cell lines. The most promising compounds were submitted to cell cycle analysis and apoptosis detection.
(44)
Thapa et al39 synthesized a series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. It was also shown by structure activity relationship study that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety (45) was important for top II inhibitory activity and 4-(5-chlorofuran-2-yl)-2-(thiophen-2-yl) moiety (46) was important to display moderate topoisomerase I and II inhibitory activity.
Kim et al40 synthesized a new series of diarylureas and amides having pyrrolo[3,2-b]pyridine scaffold (47) and their in vitro antiproliferative activity against human melanoma cell line A375 and HS 27 human fibroblast cell line with their effect of substituents on the pyrrolo[3,2-b]pyridine was investigated. Compound (47a), (47b) having 5-benzylamide substituted 4’amide moieties showed the most potent antiproliferative activity against A375.
Basnet et al41 synthesized a series of 2,6-dithienyl-4-furyl pyridine derivatives and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against several human cancer cell lines. Compound (48) showed strong topoisomerase-I inhibitory activity.
Karki et al42 synthesized a new series of 2,4-diphenyl-6-aryl pyridines containing hydroxyl group(s) at the ortho, meta or para position of the phenyl ring (49) and evaluated for topoisomerase I and II inhibitory activity along their cytotoxicity against several human cancer cell lines. Structure–activity relationship study showed that substitution of hydroxyl group(s) increased topoisomerase I and II inhibitory activity in the order of meta > para > ortho position where as hydroxyl group on the para position showed better cytotoxicity.
Liu et al43 synthesized a series of novel 2-chloro-pyridine derivatives and evaluated for potential telomerase inhibitors. Synthesized compound were assayed for telomerase nhibition by modified TRAP assay. Compounds (50) strongly inhibit telomerase with IC50 value of 0.8 ± 0.07 µM.and also exhibited some effect against gastric cancer cell SGC-7901.
Farrel et al44 synthesized a series of photoactivatable PtIV-azido complexes and studied for their photocytotoxicity. In mixed-ligand ammine/amine PtIV diazido complexes (51) cis,trans,cis-[Pt(N3)2(OH)2(NH3)(X)] where X ), 2-methylpyridine , or 4-methylpyridine , 3-methylpyridine , and 2-bromo-3-methylpyridine . It was found that trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. Substitution of NH3 ligands by MeNH2 or EtNH2 results in more potent photocytotoxicity for the all-trans complexes. These complexes i.e. 4-methylpyridine, 3-methylpyridine , and 2-bromo-3-methylpyridine were found to be toxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark.
Richardson et al45 identified structural features necessary to form Fe complexes with potent anticancer activity and generated the related 2-acetylpyridine thiosemicarbazone (HApT) analogues (52) to examine the influence of the methyl group at the imine carbon and found some of it as most potent antitumor activity. It was shown that these analogs has similar efficacy to that of most effective 2-benzoylpyridine thiosemicarbazone (HBpT) and dipyridylketone thiosemicarbazone (HDpT) ligands. Thus making HApT series the most potent antiproliferative agents.
A series of 2-arylamino-6-trifluoromethyl-3-(hydrazonocarbonyl)pyridines (53) were synthesized and evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them showed excellent growth inhibition activity in the low micromolar to nanomolar concentration range. Compound (53a) was found to be most potent and inhibited the growth of all tested cancer cell lines with nanomolar potency and did not show animal toxicity. Onnis et al46.
Abadi et al47 synthesized two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (54) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate. Compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2- dihydropyridine-3-carbonitrile (55) was the most active in inhibiting colon tumor cell growth with a IC50 of 3 µM.
Jacquenard et al48 synthesized a new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine and evaluated for their potential CDK inhibitors. Indole, 5-hydroxyindole and phenol derivatives were used to generate three substitutions of the pyridine inhibitors. Compound (55), (56) and (57) were found to inhibit CDK1 in the 0.3–0.7 micromolar range with a good selectivity over GSK-3 by kinase assays. Cytotoxicity against CEM human leukemia cells was evaluated with IC50 values in the 5–15 micromolar range.
Based on the structural analysis of fumitremorgin C (FTC) imidazoline and β-carboline amino acid benzylester 14 novel 2-substituted tetracyclic derivatives of tetrahydrocarboline (58) were prepared by Cui et al.49 They demonstrated that the exposure of MES-SA/Dx5 cells to some of the compounds resulted in significant reduction of resistance of the cells against doxorubicin. This reduced resistance was accompanied by lowering of IC50 value to doxorubicin from 1.55 ± 0.26 μmol/L to 0.33 ± 0.05 μmol/L for 2-(2-butyl)-derivative to 1.03 ± 0.22 μmol/L for 2-methyl-derivative to 0.46 ± 0.04 μmol/L for 2-benzyl-derivative to 0.98 ± 0.25 μmol/L for 2-indole-3-yl-methyl-derivative to 0.36 ± 0.03 μmol/L for 2-benzyloxycarbonylmethyl-derivative to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylethyl-derivative and to 0.77 ± 0.08 μmol/L for 2-benzyloxycarbonylamino-n-butyl-derivative. Proliferation assays of the compounds indicated four compounds that were able to inhibit the proliferation of doxorubicin resistant MES-SA/Dx5 cells. The SAR analysis revealed that the benzylester form and the tetracyclic structure of the compounds were critical for both sensitizing doxorubicin and the cellular anti-proliferative effect.
3-Ethoxycarbonyl-3-methyl-1N-substituted-2,3-dihydro-pyridin[2,3-f]indole-2,4,9-triones (59) were synthesized by Lee et al50 from 7-chloro-6-(1,1-diethoxycarbonyl-ethyl)-5,8-quinolinedione using a variety of alkyl- and arylamines. The cytotoxic activities of the synthesized compounds were evaluated by a Sulforhodamine B (SRB) assay against the following tumor cell lines: A459 (human non-small cell lung) SK-OV-3 (human ovarian) SK-MEL-2 (human melanoma), XF498 (human CNS) and HCT 15 (human colon). Almost all the derivatives mentioned above had a more potent cytotoxic effect against SK-OV-3 than etoposide. In particular, 3-ethoxycarbonyl-3-methyl-N-(4-aminophenyl)-2,3-dihydro-benz[f]indole-2,4,9-trione exhibited greater activity against all the tumor cell lines, and its cytotoxic effect against SK-OV-3 was especially higher than doxorubicin.
The N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid and a series of its ester and amide derivatives (60) were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cells by Cocco et al.51 Ester derivatives exhibited potent growth inhibitory activity with GI50 values at nanomolar concentrations. Among amide derivatives, N-anthraniloylglycinate showed moderate inhibitory activity in the full panel cancer cell line screening.
The in vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines (61) versus the standard National Cancer Institute 60 cell lines panel and of 2,6-di-[2-(heteroaryl)vinyl] pyridinium cations versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines were reported by Barresi et al.52 Antiproliferative effects in both series were particularly evident for MCF7 mammary adenocarcinoma cells. Multivariate analysis of DNA microarray data for responsive tumor cell lines suggested a mechanistic pathway involving polyamine biosynthesis and prolactin signal transduction.
A series of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidines derivatives (62) were synthesized by Reyes et al53 using a convenient synthetic route. They evaluated the isosteric replacement of methyl groups in 4-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-p-tolylpyrimidin-2-amine by trifluoromethyl groups and the isosteric substitution of the 2-methylimidazo[1,2-a]pyridin-3-yl scaffold by quinolin-4-yl or quinolin-3-yl moieties. The replacement of hydrogen by fluorine did not affect notably the cytotoxic activity and CDK inhibitor activity in this series. Quinolin-4-yl-substituted compound presented cytotoxic activity and was most effective and selective against CDK1/CycA than against CDK2/CycB. Compound which has a quinolin-3-yl moiety was CDK inhibitor but presented null cytotoxic activity. Quinolin-4-yl-substituted compounds constituted a new lead of cytotoxic and CDK inhibitor compounds from which more compelling and selective inhibitors can be designed.
Antimycobacterial activity
A new series of aryl sulfonamido conjugates of oxazolidinones (62) have been synthesized by Kamal et al54and evaluated for activity against M. tuberculosis. Further, cytotoxicity of active conjugates of this series is discussed.
A series of benzoic acid hydrazones and its nicotinyl derivatives (63) were prepared by Kumar et al55 and evaluated for their antitubercular activity towards a strain of Mycobacterium tuberculosis (MTB). Antitubercular activity was studied in Middlebrook 7H11agar medium supplemented with OADC by agar dilution method. Compound nicotinic acid N-(3,5-dinitrobenzoyl)-N’-(4-methoxy-benzylidene)-hydrazide (63a) was found to be most potent.
A series of 4-(5-Substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives (64) were synthesized by Vazquez et al56 and evaluated for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against Mycobacterium tuberculosis H37Rv and five clinical isolates (drug-sensitive and -resistant strains). Compound [4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine] (64a) was 10 times more active than isoniazid, 20 times more active than streptomycin, and 28 times more potent than ethambutol against drug-resistant strain CIBIN 112. Compound [4-(5-heptadecyl-1,3,4-oxadiazol-2-yl)pyridine] (64b) showed the same behavior as that of compound (64a).
Kumar et al57 synthesized fifteen 2-amino-6-methyl-4-aryl-8-[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitriles (65) and were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant tuberculosis (MDR-TB) and Mycobacterium smegmatis using agar dilution method. Compound 2-Amino-4-[4-(dimethylamino)phenyl]-8-(E)-[4-(dimethylamino)phenyl] methylidene-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]-pyridine-3-carbonitrile (65a) was found to be the most potent and 100 times more active than standard isoniazid against MDRTB.
[5-(Pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid arylidene-hydrazide derivatives (66) were synthesized and tested for their in vitro antimycobacterial activity by Mamolo et al.58 Some compounds showed a feasible activity against a strain of Mycobacterium tuberculosis and a strain of Mycobacterium avium.
Mamolo et al59 further synthesized 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole derivatives (67) and tested for their in vitro antimycobacterial activity. The compounds showed an interesting activity against a strain of Mycobacterium tuberculosis and a human strain of M. tuberculosis H4.
Twenty two novel 2,10-dihydro-4aH-chromeno[3,2-c]pyridin-3-yl derivatives (68) were synthesized by Sriram et al60 by reacting 3-formyl chromone (sub)-2-amino pyridines, N1-(prop-2-ynyl)arylamides in the presence of indium triflate. The compounds were evaluated their preliminary in-vitro and in-vivo activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among them N-[(4aS)-2-(3-methyl-2-pyridinyl)-10-oxo-2,10-dihydro-4aH-chromeno[3,2-c]pyridin-3-yl]methyl-4-ethylbenzenecarboxamide was found to be the most active compound in-vitro with MIC's of 0.22 and 0.07 μg/mL against MTB and MDR-TB respectively. In the in-vivo animal model it decreased the bacterial load in lung and spleen tissues with 1.11 and 2.94-log10 protections respectively at 25 mg/kg body weight dose.
Mamolo et al61 continued to work on antimycobacterial agents and synthesized N1-[1-[3-aryl-1-(pyridin-2-,3-, and 4-yl)-3-oxo]propyl]-2-pyridinecarboxamidrazone derivatives (69) and tested for their in vitro antimycobacterial activity. Some compounds showed interesting activity against a strain of Mycobacterium tuberculosis and a strain of Mycobacterium avium.
3H-1,3,4-Oxadiazole-2-thione and 3H-1,3,4-oxadiazol-2-one derivatives (70) were synthesized and tested for their in vitro antimycobacterial activity by Mamolo et al.62 Oxadiazolone derivatives showed an interesting antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H37Rv whereas the corresponding thione derivatives were devoid of activity. Molecular modeling investigations showed that the active compounds may interact at the active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway and that their binding free energy values are in agreement with their MIC values.
A series of novel enantiomerically pure spiroisoxazolidines (71) were synthesized by Kumar et al63 regioselectively by the 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones. These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the twenty two compounds screened (3S,4S,5R)-3,4-di(4-methylphenyl)-2-phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one was found to possess the maximum activity with MIC of 3.02 mM, being 2.5 times more potent than the first-line anti-TB drug ethambutol. For comparison, a series of ten enantiomerically pure spirooxazolines were also screened, among which (4R,5S)-3,4-bis(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one and (4R,5S)-4-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5] dec-2-en-10-one were found to display maximum activity with MIC of 3.25 mM.
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Received on 05.05.2011 Modified on 27.05.2011
Accepted on 07.06.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 4(12): Dec. 2011; Page 1918-1932