Synthesis of N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines as potential nonsteroidal anti‐inflammatory agents

Fourteen novel N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9 were synthesized in fair to good yields. 4‐Ethylpyridine 5 reacted with O‐mesitylenesulfonylhydroxylamine (O‐MSH) 4 to furnish N‐amino‐4‐ethylpyridinium mesitylenesulfonate 6 . The reaction of 6 with substituted acid chlorides 7 gave the stable crystalline pyridinium ylides 8a‐8n . A sodium borohydride reduction of 8 in absolute ethanol furnished the target compounds N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9a‐9n .     

Synthesis of 1‐(substituted phenylcarbonyl/sulfonylamino)‐1,2,3,6‐tetrahydropyridine‐5‐carboxylic acid diethylamides as potential anti‐inflammatory agents

Fifteen novel 1‐(substituted phenylcarbonyl/sulfonylamino)‐1,2,3,6‐tetrahydro‐ pyridine‐5‐carboxylic acid diethylamide ( 7, 15 ) were synthesized in fair to good yields via sodium borohydride reduction of the corresponding 1‐(substituted phenylcarbonyl/ sulfonylimino)‐3‐diethylcarbamoyl pyridinium ylides ( 6, 14 ) in absolute ethanol.     

Synthesis of indazol‐4,7‐dione derivatives as potential trypanocidal agents

The synthesis of new indazol‐4,7‐dione derivatives via 1,3‐dipolar cycloaddition of diazomethane with 2,3‐dimethyl‐1,4‐benzoquinone ( 2 ) and 1,4‐naphthoquinone ( 7 ) followed by N‐alkylation of the pyrazol nitrogen atom of the corresponding quinones ( 3 ) and ( 8 ) with methyl chloroacetate is described. A series of amides from esters ( 5 ) and ( 10 ) were also obtained. These compounds were tested in vitro as potential anti‐trypanosomal agents. Compounds ( 4 ) and ( 8 ) were found to have significant activity.     

Synthesis,crystal structures and anti‐inflammatory activity of four 3,5‐bis(arylidene)‐N‐benzenesulfonyl‐4‐piperidone derivatives

3,5‐Bis(arylidene)‐4‐piperidone (BAP) derivatives display good antitumour and anti‐inflammatory activities because of their double α,β‐unsaturated ketone structural characteristics. If N‐benzenesulfonyl substituents are introduced into BAPs, the configuration of the BAPs would change significantly and their anti‐inflammatory activities should improve. Four N‐benzenesulfonyl BAPs, namely (3E,5E)‐1‐(4‐methylbenzenesulfonyl)‐3,5‐bis[4‐(trifluoromethyl)benzylidene]piperidin‐4‐one dichloromethane monosolvate, C₂₈H₂₁F₆NO₃S·CH₂Cl₂, ( 4 ), (3E,5E)‐1‐(4‐fluorobenzenesulfonyl)‐3,5‐bis[4‐(trifluoromethyl)benzylidene]piperidin‐4‐one, C₂₇H₁₈F₇NO₃S, ( 5 ), (3E,5E)‐1‐(4‐nitrobenzenesulfonyl)‐3,5‐bis[4‐(trifluoromethyl)benzylidene]piperidin‐4‐one, C₂₇H₁₈F₆N₂O₅S, ( 6 ), and (3E,5E)‐1‐(4‐cyanobenzenesulfonyl)‐3,5‐bis[4‐(trifluoromethyl)benzylidene]piperidin‐4‐one dichloromethane monosolvate, C₂₈H₁₈F₆N₂O₃S·CH₂Cl₂, ( 7 ), were prepared by Claisen–Schmidt condensation and N‐sulfonylation. They were characterized by NMR, FT–IR and HRMS (high resolution mass spectrometry). Single‐crystal structure analysis reveals that the two 4‐(trifluoromethyl)phenyl rings on both sides of the piperidone ring in ( 4 )–( 7 ) adopt an E stereochemistry of the olefinic double bonds. Molecules of both ( 4 ) and ( 6 ) are connected by hydrogen bonds into one‐dimensional chains. In ( 5 ) and ( 7 ), pairs of adjacent molecules embrace through intermolecular hydrogen bonds to form a bimolecular combination, which are further extended into a two‐dimensional sheet. The anti‐inflammatory activity data reveal that ( 4 )–( 7 ) significantly inhibit LPS‐induced interleukin (IL‐6) and tumour necrosis factor (TNF‐α) secretion. Most importantly, ( 6 ) and ( 7 ), with strong electron‐withdrawing substituents, display more potential inhibitory effects than ( 4 ) and ( 5 ).     

Synthesis and isomerization of thienotriazolopyrimidine and thienotetrazolopyrimidine derivatives with potential anti‐inflammatory activity

Several derivatives containing the thieno[2,3‐d]pyrimidine system were prepared starting from 2‐amino‐4,5‐dihydronaphtho[2,1‐b]thiophene‐1‐carbonitrile ( 1 ). In particular, the synthesis and structure characterization of 8,9‐dihydronaphtho‐ [1′,2′:4,5]thieno[3,2‐e][1,2,4]triazolo[4,3‐c]pyrimidine derivatives 13–16 and their isomerization to 8,9‐dihydronaphtho[1′,2′:4,5]thieno[3,2‐e][1,2,4]‐triazolo[1,5‐c]pyrimidine derivatives 17–20 under different suitable reaction conditions were reported and verified with X‐ray analysis. Moreover, compounds 13, 14 and 22 were tested as potential anti‐inflammatory agents and derivative 14 showed potent activity in carrageenan test. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:226–234, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20114     

Synthesis,reactions, and biological study of some new thienopyrimidine derivatives as antimicrobial and anti‐inflammatory agents

Pyrimidine and thienopyrimidine derivatives play a very important role in organic chemistry because of their wide applications as bioactive compounds with multiple biological activities. However, a literature survey revealed that the merger of different groups in the thieno[2,3‐d]pyrimidine heterocyclic ring enhances its antibacterial, antifungal and anti‐inflammatory activities. This encouraged us to prepare a new series of thieno[2,3‐d]pyrimidine heterocyclic compounds and to test them as antimicrobial and anti‐inflammatory agents. These compounds have shown remarkable activity toward fungi, bacteria, and inflammation. Thus, these compounds have been prepared by the chloroacylation of 5‐amino‐4‐phenyl‐2‐(p‐tolylamino)thieno[2,3‐d] pyrimidine‐6‐carboxamide ( 4 ) using chloroacetyl chloride under neat condition to afford the target compound ( 6 ), which was used as precursor for the synthesis of a number of bioactive compounds. Thus reaction of the chloromethylpyrimidine derivative ( 6 ) with triphenylphosphine in dry benzene gave the corresponding ((4‐oxo‐9‐phenyl‐7‐(p‐tolylamino)‐3,4‐dihydropyrimido[4′,5′:4,5]thieno[2,3‐d]pyrimidin‐2‐yl)methyl) triphenylphosphonium chloride ( 7 ). Compounds 8a – 8c and 9a – 9c were obtained by the reaction of 7 with some selected aromatic aldehydes and ketones in methanol and sodium methoxide under Wittig reaction condition. The structures of the all new synthesized compounds were established on the basis of their analytical and spectral data (IR, ¹H NMR, ¹³C NMR, and MS).     

Synthesis of 1,2,5,6‐/1,2,3,6‐tetrahydropyridinyl‐tetrahydro‐cyclopentaisoxazole derivatives

Fused tetrahydrocyclopenta‐isoxazoles were synthesized by 1,3‐dipolar cycloaddition reactions with pyridinealdoxime or tetrahydropyridinealdoxime and cycloalkenes.     

Ab initio structural study of some substituted ibuprofen derivatives as possible anti‐inflammatory agents

The formation energies of a series of substituted derivatives in α‐position of ibuprofen (2‐p‐isobutyl‐phenyl‐propionic acid) are determined, at the ab initio level RHF/6‐311G** with full geometry optimization, in their neutral and anionic forms and in the gas phase and water solution to correlate their physical–chemical properties with their anti‐inflammatory activity. Conformational calculations on the acidic moiety were also performed on five of them. The ab initio methods foresee that all these molecules present two preferred conformations in which the substituting atom in α‐position is lying approximately in the aromatic ring plane, in contrast with the results obtained with semiempirical methods. In this article, the protonation energy in solution, the solvation energy, the HOMO energy of the neutral form, and the lipophilicity will be considered as possible factors of anti‐inflammatory activity. The protonation energy in solution, together with the lipophilicity, are verified to be good activity factors: The smaller the protonation energy and the lipophilicity, the larger the anti‐inflammatory activity. In contrast, the larger the solvation energy, the smaller the activity. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2004     

Novel 3‐benzoyl‐2‐piperazinylquinoxaline derivatives as potential antitumor agents

A series of new benzoylquinoxaline derivatives ( 7‐26 ) was synthesized and evaluated for antitumor activity against a panel of 60 human cell lines at the NCI of Bethesda. Among the compounds which have passed the preliminary screening, compound 23 exhibited the best profile and growth inhibition activity at 100 ‐ 10 μM. The compounds were then tested towards a folate‐dependent enzymes bio‐library including Thymidylate synthases enzymes and human Dihydrofolate reductase at 10 μM. The most of compounds exhibited a moderate inhibitory activity towards all or some of the enzymes tested with detectable inhibition constants (K_i) values in the range of 0.6‐70 μM. Compounds 21, 23, 24 showed K_i in the range of 10‐38 μM against both hDHFR and hTS.     

Synthesis of 5‐N‐glycosylaminopyrimidines. A new class of compounds with potential anti‐aids activity

Reactions between 5,6‐diaminopyrimidines 1a‐c and pentoses 2a‐e yield 5‐N‐glycosylaminopyrirnidines or 7‐polyhydroxyalkylpteridines, depending on the presence or absence of acetic acid. The “in vitro” anti‐HIV activity of 6‐amino‐2‐methoxy‐3‐methyl‐5‐N‐D‐ribosylaminopyrimidin‐4(3H)‐one 3e, 6‐amino‐2‐methoxy‐3‐methyl‐5‐N‐β‐D‐xylopyranosylaminopyrimidin‐4(3H‐one 3f, and 6‐amino‐2‐methylthio‐5‐N‐β‐L‐xylopyranosylminopyrimidin‐4(3H)‐one 3k, appears to be promising.     

Grid potential analysis,virtual screening studies and ADME/T profiling on N‐arylsulfonylindoles as anti‐HIV‐1 agents

A grid potential analysis employing a novel approach of 3D quantitative structure–activity relationships (QSAR) as AutoGPA module in MOE2009.10 was performed on a dataset of 42 compounds of N‐arylsulfonylindoles as anti‐HIV‐1 agents. The uniqueness of AutoGPA module is that it automatically builds the 3D‐QSAR model on the pharmacophore‐based molecular alignment. The AutoGPA‐based 3D‐QSAR model obtained in the present study gave the cross‐validated Q² value of 0.588, r²_pred value of 0.701, r²_m statistics of 0.732 and Fisher value of 94.264. The results of 3D‐QSAR analysis indicated that hydrophobic groups at R₁ and R₂ positions and electron releasing groups at R₃ position are favourable for good activity. To find similar analogues, virtual screening on ZINC database was carried out using generated AutoGPA‐based 3D‐QSAR model and showed good prediction. In addition to those mentioned earlier, in‐silico ADME absorption, distribution, metabolism and excretion profiling and toxicity risk assessment test was performed, and results showed that majority of compounds from current dataset and newly virtually screened hits generated were within their standard limit. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of novel methylene‐bisthiazolidinone derivatives as potential nematicidal agents

In a one pot procedure, a series of novel methylene‐bis‐thiazolidinone derivatives 5 and 6 was prepared by condensation of 5‐(3‐formyl‐4‐methoxybenzyl)‐2‐methoxybenzaldehyde 3 with mercapto acids and primary aromatic amines 4 in presence of ZnCl₂ under both microwave irradiation and conventional heating conditions. High yields are achieved even on a gram scale, while reaction times are considerably shortened under microwave irradiation compared to conventional heating conditions. Characterization of new compounds has been done by means of IR, NMR, MS and elemental analysis. The nematicidal and antibacterial activity of the compounds has also been evaluated.     

Synthesis of sydnonimine derivatives as potential trypanocidal agents

N‐(p‐Nitrophenoxy)carbonyl‐3‐morpholino‐sydnonimine (NCMS) has been prepared from 3‐morpholinosydnonimine hydrochloride. Using the Griess assay and the superoxide‐mediated reduction of ferricytochrome c, the nitric oxide (NO?) and superoxide anion (O₂?^‐) ‐ releasing properties in phosphate buffer pH 7.4 of this novel peroxynitrite donor was studied and compared with the known 3‐morpholino‐sydnonimine (SIN‐1). From compound NCMS, a series of N‐substituted sydnonimine derivatives were easily prepared that contain purine or melaminophenyl groups which specify a recognition by a trypanosomal purine transporter. The ability of these new sydnonimines to inhibit the uptake of [2³H]adenosine on Trypanosoma equiperdum was studied.     

Synthesis and anti‐HIV activity of substituted 1,2,4‐triazolo‐thiophene derivatives

A new series of substituted 1,2,4‐triazoles bearing thiophene molecules 8 and 10 has been synthesized from cycloaddition of thiophene 3‐and 2‐carbonitriles 5 and 9 , respectively, with the reactive cumulene intermediates 4 . The newly synthesized products have been evaluated for their anti‐HIV activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:443–448, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20319     

Synthesis,crystal structures and anti‐inflammatory activity of fluorine‐substituted 1,4,5,6‐tetrahydrobenzo[h]quinazolin‐2‐amine derivatives

Two fluorine‐substituted 1,4,5,6‐tetrahydrobenzo[h]quinazolin‐2‐amine (BQA) derivatives, namely 2‐amino‐4‐(2‐fluorophenyl)‐9‐methoxy‐1,4,5,6‐tetrahydrobenzo[h]quinazolin‐3‐ium chloride, ( 8 ), and 2‐amino‐4‐(4‐fluorophenyl)‐9‐methoxy‐1,4,5,6‐tetrahydrobenzo[h]quinazolin‐3‐ium chloride, ( 9 ), both C₁₉H₁₉FN₃O⁺·Cl^?, were generated by Michael addition reactions between guanidine hydrochloride and the α,β‐unsaturated ketones (E)‐2‐(2‐fluorobenzylidene)‐7‐methoxy‐3,4‐dihydronaphthalen‐1(2H)‐one, C₁₈H₁₅FO₂, ( 6 ), and (E)‐2‐(4‐fluorobenzylidene)‐7‐methoxy‐3,4‐dihydronaphthalen‐1(2H)‐one, ( 7 ). Because both sides of α,β‐unsaturated ketones ( 6 ) or ( 7 ) can be attacked by guanidine, we obtained a pair of isomers in ( 8 ) and ( 9 ). Single‐crystal X‐ray diffraction indicates that each isomer has a chiral C atom and both ( 8 ) and ( 9 ) crystallize in the achiral space group P2₁/c. The chloride ion, as a hydrogen‐bond acceptor, plays an important role in the formation of multiple hydrogen bonds. Thus, adjacent molecules are connected through intermolecular hydrogen bonds to generate a banded structure. Furthermore, these bands are linked into an interesting 3D network via hydrogen bonds and π–π interactions. Fortunately, the solubilities of ( 8 ) and ( 9 ) were distinctly improved and can exceed 50 mg ml^?1 in water or PBS buffer system (pH 7.4) at room temperature. In addition, the results of an investigation of anti‐inflammatory activity show that ( 8 ) and ( 9 ), with o‐ and p‐fluoro substituents, respectively, display more potential for inhibitory effects on LPS‐induced NO secretion than starting ketones ( 6 ) and ( 7 ).     

Cyclization of 2‐benzoylamino‐N‐methyl‐thiobenzamides to 3‐methyl‐2‐phenylquinazolin‐4‐thiones

Acylation of 2‐amino‐N‐methyl‐thiobenzamide with substituted benzoyl chlorides has been used to synthesize the corresponding 2‐benzoylamino‐N‐methylthiobenzamides. Subsequent sodium methoxide‐catalyzed ring closure gives the corresponding 3‐methyl‐2‐phenylquinazoline‐4‐thiones. These compounds were characterized by means of their ¹H‐ and ¹²C‐NMR spectra. The kinetics of the cyclization reaction has been followed with UV‐VIS spectroscopy at 100 °C in methanolic solutions of sodium methoxide.     

Synthesis of 2-hydroxy-2-phenylethylamino derivatives as potential α-adrenergic blocking agents

The synthesis of N,N'-bis[6-(2-hydroxy-2-phenylethylamino)hexyl] cystamines 4 , and N-(2-hydroxy-2-phenylethyl)-1,6-hexanediamines 6 are described. Compounds 4 were obtained by condensation of the requisite epoxide 2 with 3-(6-aminohexyl)-1,3-thiazolidine followed by dimerization with opening of the thiazolidine ring. A similar method was used for the preparation of compounds 6. In order to prepare 4j (N,N'-bis{6-[2-hydroxy-2(3,4-dihydroxyphenyl)ethylamino]hexyl}cystamine), several procedures were tested; the method of choice involved the use of 3,4-dihydroxybenzaldehyde with both hydroxy groups protected as methoxymethyl ethers.