Synthesis of some newer analogues of substituted dibenzoyl phenol as potent anti-inflammatory agents

Benzoylation of hydroxybenzophenones 1a-f affords substituted benzoyl phenyl benzoates 3a-f, which on Fries rearrangement using microwave irradiation led to a facile synthesis of solely dibenzoyl phenols 4a-f in excellent yield. The newly synthesized compounds were screened for their anti-inflammatory activity and were compared with standard drugs. Out of the compounds studied, the compound 4e showed more potent activity than the standard drugs at all doses tested.     

Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues.

Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 microM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7+/-0.04 and 0.8+/-0.09 microM, respectively. Both compounds were not toxic towards the Vero cell line.     

Synthesis and in vitro and in vivo anticancer activity of novel phenylmethylene bis-isoxazolo[4,5-b]azepines

A series of novel phenylmethylene bis-isoxazolo[4,5-b]azepine derivatives (10) have been synthesized from 3-methyl-4-nitro-5-styrylisoxazoles 6. The reaction of 6 with 3,5-dimethyl-4-nitroisoxazole (7) in piperidine afforded the Michael type adducts 8, which on treatment with different substituted chalcones in the presence of piperidine gave the Michael adducts 9. Compounds 9 underwent reductive cyclization on treatment with SnCl(2)-MeOH to afford the title compounds 10. Structure of these compounds was established on the basis of IR, (1)H NMR, (13)C NMR and Mass spectral data. The title compounds 10a-j were evaluated for in vitro and in vivo anticancer activity. Compound 10j exhibited good anticancer activity as that of standard drug Cisplatin.     

Synthesis and evaluation of novel 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5,4-b]benzopyran-4-ones as antifungal agents

An efficient synthesis of novel antifungal 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5,4-b]benzopyran-4-ones (10a-j) through 1,3-dipolar cycloaddition of all carbon 1,3-dipole (7) with substituted 3-formylchromones (8a-j) has been developed. The synthesized compounds were characterized spectroscopically and evaluated in vitro for antifungal activity against various strains. Some of the compounds 10b, 10d and 10i exhibit significant inhibitory potential against Aspergillus niger, Saccahromyces cerevisiae and Candida albicans.     

Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines

A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.     

Anti-tumor and proapoptotic effect of novel synthetic benzophenone analogues in Ehrlich ascites tumor cells

A series of substituted benzophenone analogues, (2-aroyl-4-methylphenoxy)acetamides 4a-e, have been synthesized via three-step synthesis sequence beginning with the 2-hydroxybenzophenones 1a-e in excellent yield. 1a-e on reaction with ethyl chloroacetate afford ethyl (2-aroyl-4-methylphenoxy)acetates 2a-e which on alkaline hydrolysis afforded (2-aroyl-4-methylphenoxy)ethanoic acid 3a-e. Compounds 3a-e on condensation with p-chloroaniline furnished benzophenone analogues 4a-e. In the present report, we investigated the anti-tumor and proapoptotic effect of benzophenones in Ehrlich ascites tumor (EAT) cells. Treatment of benzophenones in vivo resulted in inhibition of proliferation of EAT cells and ascites formation. Further, we demonstrate that the induction of apoptosis in EAT cells is mediated through activation of caspase-3. These results suggest a further possible clinical application of these synthetic compounds as potent anti-tumor and proapoptotic compounds.     

Synthesis, nicotinic acetylcholine receptor binding, and pharmacological properties of 3'-(substituted phenyl)deschloroepibatidine analogs

A series of 3'-(substituted phenyl)deschloroepibatidine analogs (5a-j) were synthesized. The alpha4beta2( *) and alpha7 nicotinic acetylcholine receptor (nAChR) binding properties and functional activity in the tail-flick, hot-plate, locomotor, and body temperature tests in mice of 5a-j were compared to those of the nAChR agonist, nicotine (1), epibatidine (4), and deschloroepibatidine (13), the partial agonist, varenicline (3), and the antagonist 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogs (7a-j). Unlike epibatidine and deschloroepibatidine, which are potent agonists in the tail-flick test, 5a-k show no or very low antinociceptive activity in the tail-flick or hot-plate test. However, they are potent antagonists in nicotine-induced antinociception in the tail-flick test, but weaker than the corresponding 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines.     

Synthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones

New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a-j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6 microg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15-1.5 microg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100 microg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs.     

Tetrahydropyrrolo[3,2-c]azepin-4-ones as a new class of cytotoxic compounds

Pyrroloazepinones 8a-j and 9a-j were designed by structural modification of lead compound 3. These compounds were tested on five tumor cell lines to determine the role of the azeto ring and the 2-methyl substituent in the cytotoxicity of compound 3. Our results show that compounds 8a-j (R1=CH3) have dramatically reduced cytotoxicity, resulting from the loss of the azeto moiety of lead compound 3. By contrast, azepinones 9a-j (R1=4-nitrophenyl) inhibited the proliferation of almost all cancer cell lines tested even though they lack the azeto ring. Preliminary SAR studies with these compounds revealed the importance of halogens at the para- or meta-position of the 1-phenyl moiety. Additionally, derivatives 9a (R2=H), 9e (R2=4-F), and 9g (R2=4-OMe) were selectively cytotoxic to U-251 cells. However, none of the pyrroloazepinones inhibited the enzymatic activity of CDK1/cyclin B, CDK5/p25, and GSK-3.     

Rapid synthesis of 4-benzylidene and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans as potential selective estrogen receptor modulators (SERMs) using McMurry coupling reaction

7-Methoxy-4-(4-methoxybenzylidene)-2-substituted phenyl-benzopyrans I and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans II carrying different alkylamino residues, designed as estrogen receptor (ER) binding ligands, were successfully synthesized through the McMurry coupling reaction of substituted benzaldehyde/substituted benzophenones and 2-hydroxyphenyl-7-methoxy-chroman-4-one in presence of lithium aluminum hydride and titanium (IV) chloride (LAH-TiCl(4)). Self-coupling of carbonyl reactants led to the formation of several side products. The prototypes were evaluated for their relative binding affinity (RBA), as well as their estrogenic and antiestrogenic activities. High order of estrogenic activity (>50% gain) observed with compounds 3, 7a, 7b, 7c, 8, and 10a and also their partial estrogen antagonistic activity (> or =15%) at the uterine level points toward successful designing of the compounds. Compounds 4, 7a, 7b, 7c, and 10a also possessed significant anticancer activity against human adenocarcinoma cell line (MCF-7 cell line) that may be related to their estrogen-dependent action.     

Synthesis and biological evaluation of some 5-ethoxycarbonyl-6-isopropylamino-4-(substitutedphenyl)aminopyrimidines as potent analgesic and anti-inflammatory agents

Synthesis and biological evaluation of some 5-ethoxycarbonyl-6-isopropylamino-4-(substitutedphenyl)aminopyrimidines have been achieved by cyclization of N-[2-ethoxycarbonyl-2-cyano-1-(isopropylamino)vinyl] formamidine in presence of dry HCl in dioxane followed by nucleophilic substitution of 4-chloro group with substituted aromatic amine or phenoxide. Target compounds were evaluated for their analgesic and anti-inflammatory potential by known experimental models. Some of the compounds emerged out as more potent than standard drugs. Very low ulcer index was observed for the potent compounds.     

Synthesis, structure analysis, and antibacterial activity of some novel 10-substituted 2-(4-piperidyl/phenyl)-5,5-dioxo[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine derivatives

A new series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b]-[1,2,4]benzothiadiazine arylsulfonamide derivatives (10a-j and 13a-f) was synthesized. The structures of these compounds were confirmed on the basis of spectral data, elemental analysis, X-ray analysis, and quantum chemical calculations. These compounds were evaluated for their efficacy as antibacterial agents against various Gram-positive and Gram-negative strains of bacteria. Amongst these compounds 10f and 10i were the most active compounds against Escherichia coli and 13e against E. coli as well as Bacillus subtilis. Moreover, other compounds also showed potent inhibitory activity in comparison to the standard drugs.     

An efficient synthesis and biological activity of substituted p-benzoquinones

An efficient synthesis of 2,5-diarylamino-3,6-dichloro-1,4-benzoquinone derivatives has been achieved by condensing mono substituted anilines with tetrachloro-p-benzoquinone in presence of fused sodium acetate as condensing agent under microwave irradiation without any solvent. All the synthesized compounds were tested for their antibacterial and antitumour activity using standard drugs.     

Synthesis and biological evaluation of 2-trifluoromethyl/sulfonamido-5,6-diaryl substituted imidazo[2,1-b]-1,3,4-thiadiazoles: a novel class of cyclooxygenase-2 inhibitors

A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives 15a-j have been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a-b and appropriately substituted alpha-bromo-1,2-(p-substituted)diaryl-1-ethanones 13a-h. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward COX-2 (80.6-49.4%) over COX-1 (30.6-8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory activity. These compounds also exhibited significant anti-inflammatory activity (70.09-42.32%), which is comparable to that of celecoxib in the carrageenan-induced rat paw edema method.     

Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists

A series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H1-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N1-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H1-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H1-receptor antagonistic activity with pA2 values from 7.30- 9.75 (cetirizine, pA2 value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.     

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.     

Orally active esters of dihydroartemisinin: Synthesis and antimalarial activity against multidrug-resistant Plasmodium yoelii in mice

A series of artemisinin derived esters 7a-j, incorporating pharmacologically privileged substructure, such as biphenyl, adamantane and fluorene, have been prepared and evaluated for antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis by oral route. Several of these compounds were found to be more active than the antimalarial drugs beta-arteether 4 and artesunic acid 5. Ester 7i, the most active compound of the series, provided 100% and 80% protection to the infected mice at 24 mg/kg x 4 days and 12 mg/kg x 4 days, respectively. In this model beta-arteether provided 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively.     

Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives

In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2-yl]sulfanyl]acetamide derivatives (3a-j) were obtained by the nucleophilic substitution reactions of 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) with N-(benzothiazol-2-yl)-2-chloroacetamides. The chemical structures of the compounds were elucidated by IR, (1)H NMR, (13)C NMR and FAB(+)-MS spectral data and elemental analyses. The synthesized compounds were screened for their antimicrobial activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. All compounds except compound 3h exhibited the highest antibacterial activity against P. aeruginosa. Among all compounds (3a-j), the compounds bearing 4-methoxyphenoxymethyl moiety on oxadiazole ring (3a-e) exhibited the highest inhibitory activity against C. albicans. Although compound 3j did not possess 4-methoxyphenoxymethyl moiety on oxadiazole ring, this derivative also exhibited the same level of anti-candidal activity. The compounds were also investigated for their cytotoxic effects using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Compound 3a exhibited the highest cytotoxic activity, whereas compound 3g possessed the lowest cytotoxic activity against NIH/3T3 cells.     

Microwave assisted solid support synthesis of novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepines as potent antimicrobial agents

An environmentally benign and economic synthesis of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepines is described from readily accessible substituted 2-mercapto-1-amino triazoles and substituted chalcones on basic alumina that are accelerated by exposure to microwaves. The reaction time has been brought down from hours to seconds with improved yield as compared to conventional heating. The method reported herein is devoid of the hazards of solution phase reactions. All the synthesised compounds were tested for their in vitro antibacterial and antifungal activity. Some compounds showed significant antimicrobial properties. The best activity was observed with compounds 3a, 3c, 4a and 4d.     

Aldose reductase inhibitors: flavonoids, alkaloids, acetophenones, benzophenones, and spirohydantoins of chroman

The inhibitory activity of various compounds, including 12 flavonoids, 10 alkaloids, 15 benzophenones, 5 acetophenones, and 7 spirohydantoins of chroman, was tested on rabbit lens aldose reductase, an enzyme involved in complications of diabetes. Almost all compounds tested were found to inhibit the enzyme at low concentrations (10(-5) M). The most potent inhibitor was 2R,4S-6-chloro-2-methylspiro(chroman-4,4'-imidazo-lidine+ ++)-2',5'-dione with an I50 value of 4.7 x 10(-8) M; other spirohydantoins showed similar potency. Polyhydroxybenzophenones were also potent inhibitors with an I50 value of about 10(-7) M. The possible structure-inhibitory activity relationships of the compounds tested are discussed.