Synthesis and antimicrobial activity of 2-alkenylchroman-4-ones, 2-alkenylthiochroman-4-ones and 2-alkenylquinol-4-ones

2-Alkenylchroman-4-ones, 2-alkenylthiochroman-4-ones, and 2-alkenylquinol-4-ones were prepared with very good regioselectivity by Me3SiOTf-mediated conjugate addition of alkenylmagnesium bromides and alkenyllithium compounds to chromones thiochromones, and quinol-4-ones. A number of products exhibit a considerable antimicrobial activity. The best activity, with respect to the spectrum of antimicrobial activity, was observed for 2-vinylchroman-4-ones containing an unsubstituted vinyl group and a chloride group located at the chromanone moiety.     

Analgesic activity of new synthetic thiazolidine-4-ones derivatives

Ten new synthetic thiazolidine-4-ones derivatives (5 chlorothiazolidine-4-ones, 3 methoxythiazolidine-4-ones and 2 hydoxythiazolidine-4-ones) having different substituents at R1, R2 and R3 were evaluated for their analgesic activity using different animal models and their structure activity relationship was also elucidated. Chlorothiazolidine-4-ones and methoxythiazolidine-4-ones exhibited analgesic activity in tail flick test, tail immersion test and acetic acid writhing test. C-III (chloride substituents at R1 and R2) produced higher latencies than any other compounds in tail flick test and C-I (no substituents at R1 and R2) was not effective in acetic acid writhing test. Hydroxythiazolidine-4-ones did not show analgesic activity in any of the animal models used. In conclusion, the character of substituents at R3 of thiazolidine moiety position may have an effect on the analgesic activity of thiazolidine-4-ones and either chloride or methoxy substitution may be necessary to produce analgesic activity. Two chloride substituents in a compound may increase the central analgesic activity of the compound.     

Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones

A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 microg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the muM range. One of the tested imidazolidin-4-ones was slightly more active than the parent primaquine and may represent a lead compound for the development of novel anti-P. carinii 8-aminoquinolines with increased stability and resistance to metabolic inactivation.     

Synthesis of 3-alkyl(aryl)-4-alkylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-ones and 3-alkyl-4-alkylamino-4,5-dihydro-1H-1,2,4-triazol-5-ones as antitumor agents

A series of 3-alkyl-4-phenylethylidenamino- (8) and 3-alkyl-4-(3-phenylallylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (9) was synthesized from the reaction of the corresponding 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (1), with phenylacetaldehyde and cinnamaldehyde. 3-Alkyl-4-(2-phenylethylamino)- (10) and 3-alkyl-4-(3-phenylpropylamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (11) were obtained from the selective reduction of compounds (8) and (9) with NaBH₄. The in vitro antitumor activity of the novel compounds was screened and the highest inhibition of tree tumor cell lines was observed for the compounds containing phenylethylenamino and phenylethylamino groups at position 4 of 1,2,4-triazol ring.     

Synthesis and anticancer evaluation of 3-substituted quinolin-4-ones and 2,3-dihydroquinolin-4-ones

A series of 3-aryl-5,7-dimethoxyquinolin-4-ones 8 and 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones 13 were synthesized in good yields. Demethylation under a range of conditions afforded the corresponding 5-hydroxy and 5,7-dihydroxy derivatives. Biological evaluation against a range of cancer cells lines showed that the quinolin-4-one scaffold was more cytotoxic than the reduced 2,3-dihydroquinolin-4-one scaffold. The most active monohydroxy compound 15f demonstrated 85.9–99% reduction in cell viability against the cell lines tested.     

Alternate substrate inhibition of cholesterol esterase by thieno[2,3-d][1,3]oxazin-4-ones

In a kinetic study, the interaction of bovine pancreatic cholesterol esterase (CEase) with fused 1,3-oxazin-4-ones and 1,3-thiazin-4-ones was investigated, and the compounds were characterized as alternate substrate inhibitors. Inhibition assays were performed in the presence of sodium taurocholate with p-nitrophenyl butyrate as chromogenic substrate. Strong active site-directed inhibition was detected for 2-diethylaminothieno[2,3-d][1,3]oxazin-4-ones with a cycloaliphatic chain at positions 5,6. The most potent inhibitors, compounds 3 and 4, exhibited K(i) values of 0.58 and 1.86 microm, respectively. An exchange of the ring oxygen by sulfur and the removal of the cycloaliphatic moiety as well as the replacement of the thiophene ring by benzene led to a loss of inhibitory potency. CEase has the capability to catalyze the hydrolysis of representatives of fused 1,3-oxazin-4-ones as well as the highly stable 1,3-thiazin-4-ones by using an acylation-deacylation mechanism. Hydrolyses were performed in the presence of a high enzyme concentration, and products were identified spectrophotometrically and by means of high performance liquid chromatography. The kinetic parameters V(max)I and V(max)I/K(m)(I) for the CEase-catalyzed turnover were determined. The compounds whose enzyme-catalyzed hydrolysis followed first-order kinetics (K(m)(I) > 25 microm) failed to inhibit CEase. On the other hand, inhibitors 3 (initial concentration of 25 microm) and 4 (20 microm) were hydrolyzed by CEase under steady-state conditions in the first phase of the reaction. Rate-limiting deacylation was demonstrated in nucleophilic competition experiments with ethanol as acyl acceptor wherein the conversion of compound 3 was accelerated up to an ethanol concentration of 1.5 m. The characterization of these compounds (i.e. 3 and 4) as alternate substrate inhibitors is not only based on the verification of the CEase-catalyzed hydrolysis. It also rests upon the concurrence of corresponding K(i) values obtained in the inhibition assay compared with separately determined K(m)(I) values of their enzyme-catalyzed consumption, as could be predicted from the kinetic model used in this study.     

N/C-4 substituted azetidin-2-ones: synthesis and preliminary evaluation as new class of antimicrobial agents

A series of 3-chloro-4-(3-methoxy-4-acetyloxyphenyl)-1-[3-oxo-3-(phenylamino)propanamido] azetidin-2-ones 3a-g and 3-chloro-4-[2-hydroxy-5-(nitro substituted phenylazo)phenyl]-1-phenylazetidin-2-ones 6a-h were synthesized using appropriate synthetic route. Structures of all the synthesized compounds were established on the basis of elemental analysis and spectroscopic data. The antimicrobial activity of the synthesized compounds was screened against several microbes. Several of these molecules showed potent antimicrobial activity against Bacillus anthracis, Staphylococcus aureus and Candida albicans and significant structure-activity relationship (SAR) trends.     

Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones

A series of 2-sec-amino-3H-quinazolin-4-ones (4a-p) and 4-sec-amino-2-chloroquinazolines (5a-b) have been synthesized by nucleophilic substitution reaction of 2-chloro-4(3H)-quinazolones (3) and 2,4-dichloroquinazolines (2) with amines, respectively. Most of the synthesized compounds were evaluated for antihyperglycemic activity but only 4a,b,d,j,o displayed significant reduction in blood glucose level in streptozotocin and sucrose loaded rat models.     

Benzoxazin-4-ones as novel,easily accessible inhibitors for rhomboid proteases

Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.     

2-Aryl-3,6-dialkyl-5-dialkylaminopyrimidin-4-ones as novel crf-1 receptor antagonists

The discovery, synthesis and structure-activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents     

QSAR studies on structurally similar 2-(4-methanesulfonylphenyl)pyran-4-ones as selective COX-2 inhibitors: a Hansch approach

QSAR analysis based on classical Hansch approach was adopted on two recently reported novel series of 2-phenylpyran-4-ones as selective cyclooxygenase-2 (COX-2) inhibitors. The 6-methyl derivatives of title compounds bifurcate as 3-phenoxypyran-4-ones (subset A) and 3-phenylpyran-4-ones (subset B) among series 1. Series 2 consists of 5-chloro derivatives of title compounds. Various regression equations were derived to study the influence of phenoxy and phenyl ring substituents of series 1 compounds on COX-2, COX-1 and selective COX-2 over COX-1 inhibitory activity. The best triparametric equation derived for 36 compounds of series 1 explains the hydrophobic, electronic and steric requirements for improved COX-2 inhibitory activity. QSAR model derived to explore the selective COX-2 over COX-1 inhibition showed that selectivity could be influenced by size and lipophilicity of substituents. The size of the first atom of 2 substituents appears to have negative effect on selectivity, whereas highly polar 3 substituents at R are favorable for improved selectivity. QSAR investigations on series 2 compounds revealed some interesting correlation of COX-2 inhibitory activity with calculated physicochemical properties of whole molecules. The positive logP confirms the hydrophobic interaction of series 2 compounds with COX-2 enzyme. The positive MR term indicates that an overall increase in size and polarizabilty of the molecules increases COX-2 inhibitory activity. The positive contribution of structural variable suggests biphenyl analogs are extremely potent COX-2 inhibitors.     

Design,synthesis, and antibiofilm activity of 2-arylimino-3-aryl-thiazolidine-4-ones

A series of novel 2-arylimino-3-aryl-thiazolidine-4-ones was designed, synthesized and tested for in vitro antibiofilm activity against Staphylococcus epidermidis. Among them tested, some compounds with carboxylic acid groups showed good antibiofilm activity. The antibiofilm concentration of 1x was 6.25 μM. The structure–activity relationships revealed that incorporation of 2-phenylfuran moiety could greatly enhance antibiofilm activity of thiazolidine-4-one.     

Synthesis of new bioactive venlafaxine analogs: novel thiazolidin-4-ones as antimicrobials

A one-pot, three-component, microwave irradiated and conventional solution-phase synthesis of bioactive venlafaxine analogs such as 2,3-disubstituted-1,3-thiazolidin-4-ones 3a-j under mild conditions and their characterization are reported. The novel thiazolidin-4-ones, 3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)-2-phenyl-thiazolidin-4-one 3a, 2-(2,6-difluorophenyl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3c, and 2-(furan-2-yl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3i, were characterized by the single crystal X-ray diffraction method. The cyclohexane ring of all the three molecules is in chair conformation. All the synthesized compounds were screened for their efficacy as antimicrobials in vitro by the disk diffusion and microdilution method against pathogenic strains such as Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas campestris pvs, Xanthomonas oryzae, Aspergillus niger, Aspergillus flavus, Fusarium oxysporum, Trichoderma species, and Fusarium monaliforme species. Among these compounds 3c, 3j, 3g, 3d, and 3e showed potent antimicrobial activity, when compared to standard drugs.     

Design and synthesis of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents

A new series of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-ethylphenyl)-3H-quinazolin-4-one from 4-ethyl aniline with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 2-(N'-3-pentylidene-hydrazino)-3-(4-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and was moderately more potent than the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

C-N bond formation under Cu-catalysis: Synthesis and in vitro evaluation of N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones against chorismate mutase

A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C-N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented.     

InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents

A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl(3) with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Novel 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones as IMPDH inhibitors

The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).     

Inhibition of human chymase by 2-amino-3,1-benzoxazin-4-ones

A series of 2-sec.amino-4H-3,1-benzoxazin-4-ones was evaluated as acyl-enzyme inhibitors of human recombinant chymase. The compounds were also assayed for inhibition of human cathepsin G, bovine chymotrypsin, and human leukocyte elastase. Introduction of an aromatic moiety into the 2-substituent resulted in strong inhibition of chymase, cathepsin G, and chymotrypsin. Extension of the N(Me)CH2Ph substituent by one methylene unit was unfavourable to inhibit these proteases. Towards chymase, 2-(N-benzyl-N-methylamino)-4H-3,1-benzoxazin-4-one (32) and 2-(N-benzyl-N-methylamino)-6-methyl-4H-3,1-benzoxazin-4-one (33) were found to exhibit Ki values of 11 and 17 nM, respectively, and form stable acyl-enzymes with half-lives of 53 and 25 min, respectively. Benzoxazinone 33 also inhibited the human chymase-catalyzed formation of angiotensin 11 from angiotensin I.     

Potential inhibitors of angiogenesis. Part I: 3-(imidazol-4(5)-ylmethylene)indolin-2-ones

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration.     

Synthesis of N-(1-methyl-1H-indol-3-yl)methyleneamines and 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones as potential antileishmanial agents

A series of N-(1-methyl-1H-indol-3-yl)methyleneamines and eight new 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized and screened for their antileishmanial activity against Leishmania major. 3,3-Diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized by the Staudinger's ketene-imine cycloaddition employing two 2-diazo-1,2-diarylethanones as the precursors of diarylketenes. A marked improvement in anti-parasitic activity is observed by transformation of the methyleneamines to azetidin-2-ones in seven out of eight compounds. Two compounds displayed antileishmanial activity comparable to that of the clinically used antileshmanial drug, amphotericine B.