Anticonvulsant properties of 3-oxo- and 3-imino-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides

Selectively substituted 3-oxo-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides (2, four examples), and 3-imino-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides (3, eight examples) have been evaluated in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole seizure threshold (scMet), and rotorod (Tox) tests. These compounds can be considered as sulfonyl analogues of hydantoins (1). In those cases where comparison between 1 and 2 (or 1 and 3) was possible, replacement of the central carbonyl group in 1 by a sulfonyl moiety led to a significant reduction or abolition of the anticonvulsant activity.     

Potential anticonvulsants. 11. Synthesis and anticonvulsant activity of spiro[1,3-dioxolane-2,3'-indolin]-2'-ones and structural analogues

A number of spiro[1,3-dioxolane-2,3'-indolin]-2'-ones were synthesized and tested for anticonvulsant activity in the maximal electroshock seizure (MES) and pentylenetetrazole seizure threshold (sc-Met) tests. 5'-Chlorospiro[1,3-dioxolane-2,3'-indolin]-2'-one was the most active compound in the MES test and had ED50 = 27.97 mg/kg. Structural analogues spiro[1,3-dioxane-2,3'-indolin]-2'-one, spiro[1,3-dithiolane-2,3'-indolin]-2'-one, spiro[indoline-3,2'-[1,3]-oxathiolan]-2-one, and 3,3-dimethoxyindolin-2-one were also evaluated for anticonvulsant activity. Almost all compounds submitted for screening exhibited the ability to protect mice against electrically and chemically induced seizures. The ED50 and TD50 values for some of the title compounds are reported. Anticonvulsant screenings were carried out through NINCDS, NIH.     

1-[3-(Diarylamino)propyl]piperidines and related compounds, potential antipsychotic agents with low cataleptogenic profiles

On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).     

Synthesis, physicochemical and anticonvulsant properties of new N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part II

A series of N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane- (1a-e), 2-azaspiro[4.5]decane- (2a-e) and 6-methyl-2-azaspiro[4.5]decane-1,3-dione (3a-e) were synthesized and tested for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. To explain the possible mechanism of action, the most active compounds N-(3-methylpyridine-2-yl)-2-azaspiro[4.4]nonane-1,3-dione (1b), N-(3-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2b), N-(4-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2c), and N-(3-methylpyridine-2-yl)-6-methyl-2-azaspiro[4.5]decane-1,3-dione (3b) were tested in vitro for their influence on voltage-sensitive calcium channel receptors, however, they revealed low affinities. For all synthesized compounds the lipophilicity was determined by use of RP-TLC method. The correlation between the lipophilicity and anticonvulsant activity was obtained--the higher the lipophilicity the stronger the anticonvulsant efficacy.     

Functionalized DL-amino acid derivatives. Potent new agents for the treatment of epilepsy

Structural analogues of the potent known anticonvulsant agent N-acetyl-DL-alanine N-benzylamide (1a) have been prepared (16 examples). The pharmacological activities of these products were evaluated in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole seizure threshold (sc Met), and the rotorod (Tox) tests. The median effective doses (ED50) and the median toxic doses (TD50) for the most active compounds by both intraperitoneal and oral administration are reported. The most active compounds were N-acetyl-DL-phenylglycine N-benzylamide (1d) and N-acetyl-DL-alanine N-m-fluorobenzylamide (1m) along with the parent compound 1a. The ED50 values in the MES test for these three compounds compared well with phenobarbital, while their high TD50 values contributed to their large protective indexes, which approached that of phenytoin. When tested against four convulsant agents, compounds 1a and 1d displayed activity profiles significantly different from those reported for conventionally used antiepileptic drugs.     

New thiazolo[4,5-d]pyrimidine derivatives as potential antimicrobial agents

In this study, by starting from ethyl 4-amino-2,3-dihydro-3-phenyl-2-thioxothiazole-5-carboxylate (1), three compounds having 2,3-dihydro-3-phenyl-5-mercapto-6-alkyl/phenyl-2-thioxothiazolo[4,5- d]pyrimidin-7(6H)-one (2a-c) structure and their 5-(4'-nonsubstituted/-substituted benzoylmethyl)thio derivatives (3a-l) were synthesized. The antimicrobial activities of the synthesized compounds were investigated against some bacteria and fungi using the microdilution method. 2,3-Dihydro-3,6-diphenyl-5-(4'-bromobenzoylmethyl)thio-2-thioxothiazolo [4,5-d]pyrimidin-7(6H) one (3k) possessing remarkable activity against Gram-positive bacteria and yeast like fungi was found to be the most active compound in this series.     

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substituted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarbazides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicarbazone compounds were compared at different doses, 2-(1H-imidazole-1-yl)-1-(2-naphthyl)ethane-1-one N-(3-chlorophenyl)thiosemicarbazone (3) and 2-(1H-imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl) thiosemicarbazone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1-(1-biphenyl)ethane-1-one N-(4-methylphenyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4-dichlorophenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemicarbazone compounds showed neurotoxicity at higher doses.     

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.     

Synthesis, characterization & anticonvulsant activity of amide derivatives of 4-amino-1,2-naphthoquinone

In the present study, 4-amino-1,2-naphthoquinone analogues were synthesized and characterized by spectroscopic (FT-IR, ¹H NMR and ¹³C NMR) and elemental analysis. The synthesized compounds were evaluated for anticonvulsant activity by the maximal electroshock (MES) test and subcutaneous pentylenetetrazole (sc. PTZ) test, the most widely employed seizure models for early identification of anticonvulsant candidates, whereas their neurotoxicity was examined by rotarod test. Compounds were administered to animals at different concentrations (10, 20 & 40 mg/kg) by intraperitonial (i.p.) route and the % seizure protection was measured. The pharmacological results revealed that majority of compounds were effective in MES and sc. PTZ tests. Compounds N-(1,2-dihydro-1,2-dioxonaphthalen-4-yl)butyramide (4) and N-(1,2-dihydro-1,2-dioxonaphthalen-4-yl)-3-methylbutanamide (6) were active at the dose 40 & 20 mg/kg, respectively, while compounds N-(1,2-dihydro-1,2-dioxonaphthalen-4-yl)hexanamide (7) and 4-acetamido-N-(1,2-dihydro-1,2-dioxonaphthalen-4-yl)benzamide (10) were active at the dose 10 mg/kg and emerged as the most active compounds of the series. These compounds showed anticonvulsant effect comparable to phenytoin which was used as reference antiepileptic drug. The above-mentioned compounds have diminutive neurotoxic effects so they can move on next phase of anticonvulsant drug development.     

Adenosine deaminase inhibitors. Synthesis and biological evaluation of (+/-)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d] [1,3]diazepin-8-ol and some selected C-5 homologues of pentostatin

The synthesis of several analogues of (8R)-3-(2-deoxy-beta-D-erythro- pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin, 1a) is described. Ring closure of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (3) with triethyl orthoacetate or triethyl orthopropionate gave the C-5 methyl and ethyl ketoaglycons, 6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (4b) and 5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4c), respectively. Stannic chloride catalyzed condensation of the pertrimethylsilyl derivatives of 4b and 4c with a protected glycosyl halide afforded anomeric mixtures of ketonucleosides 3-(2-deoxy-3,5-di-O-p-toluoyl-beta- and -alpha-D-erythro-pentofuranosyl)-6,7-dihydro-5-methylimidazo[4,5-d] [1,3]diazepin-8(3H)-one (5b and 6b) and 3-(2-deoxy-3,5-di-O-p-toluoyl)-beta- and -alpha-D-erythro-pentofuranosyl)-5-ethyl-6,7-dihydroimidazo[4,5-d]- [1,3]diazepin-8(3H)-one (5c and 6c), respectively. Subsequent separation of the anomers, followed by deprotection and reduction of 5b, 6b, and 5c, afforded the respective 8R and 8S isomers. Stannic chloride catalyzed condensation of pertrimethylsilyl ketoaglycon 4a with 2-(chloromethoxy)-1-(p-toluoyloxy) ethane to give ketonucleoside 6,7-dihydro-3-[[2-(p-toluoyloxy)ethoxy] methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one (9a) was followed by deprotection to 6,7-dihydro-3[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3] diazepin-8(3H)-one (9b) and then reduction to the racemic acyclic pentostatin analogue (+/-)-3,6,7,8-tetrahydro-3-[ (2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol (2). Ki values for the in vitro adenosine deaminase (EC 3.5.4.4; type I; calf intestinal mucosa) inhibitory activities of 1b, 1c, and 2 were determined to be 1.6 X 10(-8), 1.5 X 10(-6), and 9.8 X 10(-8) M, respectively. When compounds 2 and 9b were tested in combination with vidarabine against herpes simplex virus, type 1, in an HEp-2 plaque reduction assay, only compound 2 was able to potentiate the antiviral activity of vidarabine.     

Synthesis and anticonvulsant activity of acetylenic quinazolinone derivatives

Acetylenic derivatives of quinazolinones and quinazolinediones were synthesized and evaluated for their anticonvulsant activity. Most compounds displayed seizure-antagonizing activity in the maximal electroschock test (MES test) in most cases associated with little or no acute neurotoxicity determined in the rotorod test. Only three compounds exhibited significant activity in the seizure threshold test with subcutaneous pentylenetetrazole (scMet test). Based on the ED50 in the MES test, 1,3-bis-(prop-2-ynyl)-quinazoline-2,4-(1H,3H)-dione(9a) was about ten-fold less active than phenytoin or carbamazepine but about as active as mesuximide.     

Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids

Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).     

anticonvulsant and toxicity evaluation of newer 4H-benzo[1,4]oxazin-3-ones: The effect of two hydrogen bonding domains

A series of (Z)-2-(substituted aryl)-N-(3-oxo-4-(substituted carbamothioyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) hydrazine carboxamides (6a-r) was synthesized using 2-amino-5-nitrophenol as a starting material. All the synthesized compounds possessed two hydrogen-bonding domains and their effect on the activity was studied thereof. The anticonvulsant activity was assessed by the maximal electroshock test (MES), subcutaneous pentylenetetrazole test (scPTZ) and intraperitoneal thiosemicarbazide test (ipTSC). Compounds (6b, 6h, 6i, and 6p) were found to be the most potent of the series as they showed 83-100% protection in the MES test. They also displayed considerable activity in the chemically induced seizure tests. Most of the tested compounds were devoid of the neurotoxic and hepatotoxic effects.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Synthesis of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-triazolo[4,3-a]quinolin-1(2H)-ones with anticonvulsant activity

A series of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests with intraperitoneally injected mice. Among the synthesized compounds, 2-propionyl-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one 4b was the most active one and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 8.2 mg/kg, median toxicity dose (TD(50)) of 318.3 mg/kg, and the protective index (PI) of 39.0 which is much greater than the PI of the reference drugs phenytoin and carbamazepine.     

Synthesis and anticonvulsant activity of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

Starting from 6-hydroxy-3,4-dihydro-1H-quinoline-2-one, a series of 1-substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines was synthesized and their structures were characterized using IR, 1H-NMR, MS, and elemental analysis techniques. Anticonvulsant activity was evaluated in the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scMet) test, and rotarod neurotoxicity test. The most active compound was 7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline 4a. Its ED50 in the MES and scMet tests was 17.3 and 24 mg.kg-1, respectively. The safest compound was 4 g, 1-phenyl-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline, with TD50 and protective index (PI) (PI=TD50/ED50) values of greater than 300 mg.kg-1 and 13, respectively. The PI value of compound 4 g was better than that of most marketed drugs. Structure-activity relationships are also described in this paper.     

Synthesis and antibacterial activity of thiosemicarbazones of 3-acylquinolones]

Oxidation of 3-acetyl derivatives of 3-acetyl-1-ethyl-1,4-dihydro-6,7-methylenedioxyquinoline-4-one (VIc) and 3-acetyl-7-chloro-1-ethyl-6-fluoro-1,4-dihydroquinoline-4-one (VId) with selenium dioxide provided the corresponding acids, [1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-yl]glyoxylic acid (VIe) and [7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-yl]glyoxylic acid (VIf), respectively. Reactions of compounds VIc--VIf with thiosemicarbazide yielded the respective thiosemicarbazones of 3-acetyl-1-ethyl-1,4-dihydro-6,7-methylenedioxyquinoline-4-one (VIIa), 3-acetyl-7-chloro-1-ethyl-6-fluoro-1,4-dihydroquinoline-4-one (VIIb), [1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-yl]glyoxylic acids (VIId). The compounds showed no significant in vitro antibacterial activity.     

Synthesis, physicochemical and anticonvulsant properties of new N-4-arylpiperazin-1-yl amides of (2-aza-1,3-dioxospiro[4.4]non-2-yl)- and [4.5]dec-2-yl)-propionic acid

In continuation of the search of new anticonvulsants, a series of N-4-arylpiperazin-1-yl 2-aza-1,3-dioxospiro[4.4]non-2-yl- (5-8) and [4.5]dec-2-yl- (9-15) propionamides, structurally related to the previously described N-4-arylpiperazin-1-yl amides of 2-aza-1,3-dioxospiro[4.5]dec-2-yl-acetic acid, were synthesized. The designed compounds 5-15 were prepared by condensation of the formerly obtained (2-aza-1,3-dioxospiro[4.5]dec-2-yl)- (3) and (2-aza-1,3-dioxo[4.4]non-2-yl)-(4) propionic acids with the appropriately substituted 4-arylpiperazines, in the presence of the N,N-carbonyldiimidazole (CDIM) reagent. All the compounds were tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Several compounds 7-10, 13 and 14 revealed protection in the MES screening.     

Dihydropyridazinone cardiotonics: the discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H -indol-2- one

We discovered that 6 (N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide) is a potent positive inotrope in dogs, and we have prepared several lactam analogues of this agent. These included 16 (1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one), 32 (the analogous quinolin-2-one), and 37 (the analogous benzazepin-2-one). The inotropic ED50's of these compounds were 24, 3.3, and 5.2 micrograms/kg, respectively, after iv administration to pentobarbital-anesthetized dogs. Compound 20 (LY195115, 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-i ndol-2- one), the geminal dimethyl analogue of 16, was 3.5-fold more potent than 16 when administered iv (ED50 = 6.8 micrograms/kg). However, the most profound effect of the geminal alkyl substitution was on oral activity. The approximate ED50's of 20 and 16 after oral administration to conscious dogs were 25 and 400 micrograms/kg, respectively. The increase in contractility produced by 25 micrograms/kg of 20 was maximally sustained in excess of 8 h. Thus, 20 is one of the most potent and long-acting oral inotropes described to date.     

Facile diversity-oriented synthesis and antitubercular evaluation of novel aryl and heteroaryl tethered pyridines and dihydro-6H-quinolin-5-ones derived via variants of the Bohlmann-Rahtz Reaction

The diversity oriented synthesis of substituted pyridines and dihydro-6H-quinolin-5-ones tethered with aryls and heteroaryls was achieved in very good yields through CeCl(3)·7H(2)O-NaI catalyst via variants of the Bohlmann-Rahtz reaction. β-Enaminones derived from various aryl and heteroaryl methyl ketones were regioselectively reacted with ethyl acetoacetate or 5,5-dimethylcyclohexane-1,3-dione or 4,4-dimethylcyclohexane-1,3-dione and ammonium acetate refluxing in 2-propanol. Applicability of nontoxic cerium catalyst, high reactivity with wide range of aryl and heteroaryl β-enaminones leading to diverse analogues, operational simplicity, and shorter reaction time at comparatively low temperatures are prominent features of the developed protocol. These synthesized substituted pyridines and dihydro-6H-quinolin-5-one analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 48 compounds screened, six compounds 2-(5-chlorothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{13,2}, 2-(5-bromothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{14,2}, 2-(5-chloro thiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{13,3}, and 2-(5-bromothiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{14,3}, 7,7-dimethyl-2-(naphthalen-2-yl)-7,8-dihydroquinoline-5(6H)-one 4{6,2}, 6,6-dimethyl-2-(naphthalen-2-yl)-7,8-di hydroquinolin-5(6H)-one 4{6,3} resulted as the most promising antitubercular agents.