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Synthetic and biological studies of pyrazolines and related heterocyclic compounds
1st Heterocyclic Update
*Corresponding author. Tel.: +91 175 2287607; fax: +91 175 2283073 yusuf_sah04@yahoo.co.in (Mohamad Yusuf)
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Received: ,
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This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Available online 1 October 2011
Peer review under responsibility of King Saud University.
Abstract
This review provides a comprehensive survey relating to the synthesis and biological applications of pyrazolines and related heterocycles in the last five years (2007–2011). These compounds are usually prepared from the cyclization of chalcones with hydrazine and its derivatives under the alcoholic conditions. The major incentive behind the synthesis of these compounds was the immense biological activities associated to these heterocyclic derivatives. The aim of this review is to find out different methods for the synthesis of pyrazoline derivatives.
Keywords
Pyrazole
Bispyrazoline
Chalcones
Bischalcone
Cyclocondensation
1 Introduction
The development of a clean procedure for the preparation of heterocyclic compounds is a major challenge in modern heterocyclic chemistry in view of the environmental, practical and economic issues. Pyrazolines are an important class of heterocyclic compounds containing two nitrogen atoms in the five membered ring. The substituted 2-pyrazolines have found application as activators for polymerization (Bauer and Piatert, 1981), dyes for wool, nylon (Evans and Waters, 1978), as electro photographic conductors (Murayama and Mater, 1981) and as wavelength shifters in liquid and polymer scintillation (Poduzhailo et al., 1979). Pyrazoline derivatives are the electron rich nitrogen heterocycles which play an important role in the diverse biological activities. These heterocyclic compounds widely occur in nature in the form of alkaloids, vitamins, pigments and as constituents of plant and animal cell. Considerable attention has been focused on the pyrazolines and substituted pyrazolines due to their interesting biological activities. These compounds have been found to possess anti-fungal (Korgaokar et al., 1996), anti-depressant, anticonvulsant (Palaska et al., 2001; Rajendra et al., 2005; Ozdemir et al., 2007; Ruhogluo et al., 2005), anti-inflammatory (Udupi et al., 1998), anti-bacterial (Nauduri and Reddy, 1998) and anti-tumor (Taylor and Patel, 1992) properties. The pyrazole moiety is found in blockbuster drugs such as celecobix (Penning et al., 1997), sildenafil (Terrett et al., 1996) and rimonabant (Seltzmann et al., 1995). Recently a very important review has been published upon the studies of pyrazoline compounds (Kumar et al., 2009).
2 Discussion
1,3,5-Triaryl-2-pyrazolines 3 (Li et al., 2007) have been prepared through the reaction of chalcones and phenyl hydrazine hydrochloride (Scheme 1) in the presence of sodium acetate-acetic acid aqueous solution under ultrasound irradiation.
3,4,5-Metalated pyrazoles 6 and 7 were synthesized (Gonzalez-Nogal et al., 2007) by 1,3-dipolar cycloadditions of silyl, disilyl, and silylstannylacetylenes with N-phenylsydnone or trimethylsilyldiazomethane (Scheme 2).
The heterocyclics 5-(-4-(Substituted)phenyl)-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-toluidinomethane thione 12 and 5-(substituted) phenyl-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-methoxyanilino methane thione 13 were obtained (Ali et al., 2007) by the reaction between hydrazine hydrate and chalcones 10 followed by condensation with the appropriate aryl isothiocyanate (Scheme 3).
Synthesis of 5-substituted-3-dimethoxyphosphono-pyrazoles 16 and 17 and 2-pyrazolines 20 and 21 has been accomplished (Conti et al., 2007) through 1,3-dipolar cycloaddition of a suitable nitrile imine to monosubstituted alkynes 15 and alkenes 19 as shown in Scheme 4.
An interesting method ha been reported by Alexander V. Shevtson et al. (2007) for the synthesis of 1-mono- and 1,2-diacylpyrazolidines 23 as well as 1-arylsulfonyl-2-pyrazolines 24 which is described in Scheme 5.
The compounds 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones 30 have been prepared by the oxidation of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substitutedphenyl)-4-bromo-2-pyrazolines 29 with dimethylsulfoxide (Mishra et al., 2007). The later has been released via the reactions sequence which is depicted in Scheme 6.
An efficient method (Joshi et al., 2008) has been reported regarding the synthesis of 5-substituted-2-thiol-1,3,4-oxadiazoles 32 according to the protocol as shown in Scheme 7.
Braulio Insuasty et al. Insuasty et al. (2008) have synthesized new bis-3,5-diphenylpyrazolines 36 from the cyclization of bischalcones 35 with hydrazine hydrate in acetic acid medium. The later was prepared by the Claisen–Schmidt reaction of bis-acetophenone 35 with suitable aromatic aldehydes (Scheme 8).
Some biologically significant bis-heterocycles (Jayashankra and Lokanatha, 2008) bearing pyrazoline moieties 40 have been synthesized starting from pyrazolyl aldehyde 37 through the reaction sequence as described in Scheme 9.
3,5-Diaryl carbothioamide pyrazolines 44–46 designed as mycobactin analogs (mycobacterial siderophore) were reported to be potent antitubercular agents under iron limiting condition (Jayaprakash et al., 2008). These compounds were obtained via the usual protocol as given in Scheme 10.
1,3,5-Trisubstituted pyrazolines 47 have been oxidized to the corresponding pyrazoles 48 in high yield with tris(4-bromophenyl)aminium (TBPA) hexachloroantimonate in chloroform at room temperature (Gang et al., 2008) (Scheme 11).
A number of 1,3-diaryl-5-(cyano-,aminocarbonyl-andethoxycarbonyl-)-2-pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione and 1,3,4,5-tetraaryl-2-pyrazoline derivatives 52 were prepared (Abunada et al., 2008) by the reaction of nitrilimine with different dipolarophilic reagents (Scheme 12).
Recently the Michael accepters (Padmavathi et al., 2008), 1-arylsulfonyl-2-styrylsulfonylethenes 53 have been used as synthons to develop bis-pyrroles 55, pyrrolyl pyrazolines 56 and pyrrolyl isoxazolines 57 by 1,3-dipolar cycloaddition of tosylmethyl isocyanide, nitrile imines and nitrile oxides (Scheme 13).
A facile, InCl3 and/or DABCO mediated synthesis (Krishna et al., 2008) of 3,5-disubstituted pyrazolines 61 and pyrazoles 63 and 66 has been achieved by 1,3-dipolar cycloaddition of ethyl diazoacetate (EDA) with various activated olefins 60 under solvent-free conditions at ambient temperature (Schemes 14 and 15).
A series of pyrazoline derivatives 69 were designed and prepared (Zhao et al., 2008) by introducing methoxyacrylate pharmacophore into the scaffold of 1-acetyl-3,5-diarylpyrazoline 68 according to the method which is shown in Scheme 16.
The synthesis of aryl-substituted pyrazolines 73 has been developed by Matthias Beller and co-workers (Alex et al., 2008) in which phenylhydrazine reacts with 3-butynol 71 in the presence of a catalytic amount of zinc triflate to give pyrazoline derivatives through the involvement of hydrazone 72 (Scheme 17).
A series of 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives 75 were synthesized by Bao-Xiang Zhao et al. Xia et al. (2008) (Scheme 18) and the effects of all the compounds on A549 cell growth have also been investigated. The results showed that all compounds had almost inhibitory effects on the growth of A549 cells. The study on structure activity relationships and prediction of lipophilicities of compounds showed that compounds with Log P values in the range of 4.12–6.80 had inhibitory effects on the growth of A549 cell and the hydrazones derived from salicylaldehyde had much more inhibitory effects.
The analgesic and anti-inflammatory properties of novel 3/4-substituted-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carboxyamidepyrazoles 77 (where 3/4-substituent are H/H, Me/H, Et/H, Pr/H, i-Pr/H, Bu/H, t-Bu/H, Ph/H, 4-Br-Ph/H and H/Me) were determined (Sauzem et al., 2008) and these compounds were synthesized in the exploration of the bioisosteric replacement of benzene present in salicylamide with a 5-trifluoromethyl-4,5-dihydro-1H-pyrazole scaffold (Scheme 19).
A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives 81 were synthesized (Chimenti et al., 2008) from the usual reaction of chalcone 80 with hydrazine hydrate (Scheme 20).
The cyclocondensation reaction (Almeida da Silva et al., 2008) of 4-methoxy-1,1,1-trifluoro[chloro]-4-(substituted)-alk-3-en-2-ones 82 and isoniazid (INH) led to the formation of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazole 83 (Scheme 21).
One pot and regioselective synthesis (Bonacorso et al., 2009) of a novel series of 3-aryl(heteroaryl)-5-triflouromethyl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-carbohydrazides 86 and bis-(3-aryl-5-triflouromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)methanones 87 have been reported from the reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-triflouro-3-en-2-ones 85 under the reaction conditions which are shown in Scheme 22.
Eva Frank et al. (2009) have investigated a highly diastereoselective Lewis acid induced intramolecular 1,3-dipolar cycloadditions of alkenyl phenylhydrazones 90 (containing various substituents on the aromatic ring) under fairly mild conditions to furnish andros-5-ene-fused arylpyrazolines 93 in good to excellent yields (Scheme 23).
The compounds 100 and 101 have been prepared from the cyclization of chalcone 99 with hydrazine hydrate and guanidine respectively (Solankee et al., 2009). The compounds 99 were released from the condensation of ketone 98 with suitable substituted aromatic/heterocyclic aldehydes under alkaline conditions. The compound 98 was obtained via two step reaction starting from 96 as shown in Scheme 24.
The cyclization reaction (Zsoldos-Mady et al., 2009) of 1-phenyl-3-ferrocenyl-2-propen-1-one 102 with substituted hydrazines led to the formation of pyrazolines 103–107. The nature of substitutent on the hydrazine moiety had profound effect upon the products distribution in these reaction. The reaction with methylhydrazine could provide two regioisomeric pairs of pyrazolines 104, 105 and 107 and pyrazoles 103 and 106 (Scheme 25).
The compound 1,2 pyrazolines 113 have been prepared (Gowramma et al., 2009) because of the interesting pharmacological properties associated to these substrates (Scheme 26). The synthesized compounds were screened for their anti-cancerous activity. It was found that 1-(bis-N,N-(chloroethyl)-amino acetyl) 3,5-disubstituted-1,2-pyrazoline showed anticancer activity.
A variety of bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides) 115 and bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides) 116 were prepared (Barsoum and Girgis, 2009) via the reaction of bis(2-propen-1-ones) 114 with thiosemicarbazide/KOH and semicarbazide/AcOH respectively (Scheme 27).
Novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl) propenone 119 had been prepared (Bandgar et al., 2009) by the Claisen–Schmidt condensation of 1-(2,4-dimethoxy-phenyl)ethanone 117 and substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes 118 (Scheme 28). The later compounds were obtained by the Vilsmeir–Haack reaction of acetophenone phenylhydrazones.
1-Aryl-4,4-dichlorobut-3-en-1-ones 123 were efficiently synthesized (Guirado et al., 2009) by the treatment of acetophenones with anhydrous chloral, followed by dehydration and reductive dechlorination (Scheme 29). The compounds 122 reacted with hydrazine hydrate and methylhydrazine to give 127 and 128 respectively in high to quantitative yields.
Mohamed Abdel-Aziz et al. (Shoman et al., 2009) have reported the synthesis of 3,5-diaryl-2-pyrazoline derivatives 132 which were obtained via the reaction of various chalcones 131 with hydrazine hydrate in ethanol. The compounds 132 were further converted to various N-substituted derivatives 133–138 according to the reaction conditions and protocol as given in Scheme 30.
Effective syntheses of endo- and exocyclic α,β-unsaturated ketones as C⚌C dipolarophiles (Mernyak et al., 2009) were carried out in the estrone series. 1,3-dipolar cycloadditions of unsaturated ketones of estrone 3-methyl and 3-benzyl ether with nitrilimines stereoselectively furnished two regioisomers of new condensed pyrazolines 140 and 141 in a ratio of 2:1 (Scheme 31).
The reaction (Khode et al., 2009) of various substituted 3-aryl-1-(3-coumarinyl)propan-1-ones 147 with phenylhydrazine in the presence of pyridine led to the synthesis of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines 148 (Scheme 32).
1-[(Benzoxazole/benzimidazole-2-yl)thioacetyl]pyrazoline derivatives 154 were obtained (Kaplancikli et al., 2009) by reacting 3,5-diaryl-1-(2-chloroacetyl)pyrazolines 153 with 2-marcaptobenzoxazole/benzimidazole. The later compounds were released starting from benzaldehydes 149 and 150 according to the reactions sequence which are depicted in Scheme 33.
Recently, N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines 158 have been prepared (Pathak et al., 2009) from the cyclocondensation of 1,5-substituted diphenyl-1,4-pentadien-3-ones 157 with hydrazine hydrate and a cyclizing agent such as acetic acid in ethanol (Scheme 34).
Tricyclic fused pyrazolines 160 have been synthesized (Scheme 35) from the reaction of 3-arylidenechromanones/thiochromones 159 with (4-carboxyphenyl)hydrazine in hot anhydrous pyridine solution (Levai and Jeko, 2009).
The oxidation of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 161 to the corresponding pyrazoles 162 has been achieved by utilizing tetrabromine-1,3,5,7-tetrazatricyclo[3.3.1.1]decane complex, Br4-TATCD, in glacial acetic acid under microwave irradiation and conventional thermal condition (Scheme 36) at room temperature with excellent yields (Azarifar and Khosravi, 2009).
The reaction (Singh et al., 2009) of dibenzalacetone 165 with hydrazine hydrate and formic acid yielded a novel 2-pyrazoline 166 (Scheme 37).
The reaction of cholest-5-en-7-one 167 with thiosemicarbazide in sodium ethoxide (Scheme 38) afforded 2′-thiocarbamoyl-cholest [5,7-cd] pyrazoline 168, [X=H] 2′-thiocarbamoyl-3β-acetoxycholest [X=OAc] pyrazoline 168, and 2′-thiocarbamoyl-3β-chloro cholest pyrazoline [X=Cl] 168 respectively (Shamsuzzaman Khan and Alam, 2009).
The synthesis of pyrazolines 170 was carried out to study the effect of bromine on the biological activity (Kumar et al., 2009). These compounds were brominated by using bromine in acetic acid (Scheme 39). All synthesized compounds were tested for antimicrobial activity against gram positive and gram negative bacteria. It was found that most of the compounds were found active against all bacteria except Escherichia coli.
The substituted carboxylic acid hydrazides 171 reacted with ethenetetracarbonitril in dimethyl formamide (Scheme 40) with the formation of diacylhydrazines 172 and 5-amino-1-substiuted pyrazole-3,3,4-tricarbonitriles 173 (Abdel-Aziz et al., 2009).
A new series of 1H-3-(4′-substituted phenyl)-5-(6″-methoxy napthaline)-2-pyrazolines 179 and 1H-3-(4′-substituted phenyl)-5-(6″-methoxy napthaline)-2-isoxazolines 178 have been synthesized (Jadhav et al., 2009) from the reaction of 1-(4′-substituted phenyl)-3-(6″-methoxynapthaline)-2-propene-1-one 177 with hydrazine hydrate and hydroxylamine hydrochloride respectively (Scheme 41).
The enaminonitrile 181 was used as the key intermediate for the synthesis of polyfunctionally substituted heterocycles pyrazoles 184 (Scheme 42) incorporating benzothiazole 183 moiety via its reactions with some N-nucleophiles (Bondock et al., 2009).
Recently Sheena Shashikanth et al Rai et al. (2009) have reported the synthesis of a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles 189 from cyclization of substituted benzoic acid N-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide 188 with phosphorousoxychloride (Scheme 43).
A new class of heterocycles, substituted pyrazoles 193, isoxazoles 192, pyrimidines 194, thioxopyrimidines 195 were released from the Michael adducts 190, 2-(1,2-diaroylethyl) malononitrile and 2-(1,2-diarylsulfonylethyl) malononitrile (Padmaja et al., 2009) which subsequently underwent cyclocondensation with the appropriate nucleophiles to produce the final compounds (Scheme 44).
The compounds 1-(4-methylcoumarinyl-7-oxyacetyl)-3,5-dimethyl-4(arylazo)pyrazoles 198 and 1-(4-methylcoumarinyl-7-oxyacetyl)-3-methyl-4-(substituted phenyl) hydrazono-2-pyrazolin-5-ones 199 were prepared (Manojkumar et al., 2009) according to the protocol which is described in Scheme 45.
The thiocarbamoyl derivative 200 was reacted with hydrazine hydrate (Fadda et al., 2009) to afford the pyrazole derivatives 201 (Scheme 46).
A new series of chalcones 205 were synthesized (Revanasiddappa et al., 2010) from the condensation of simple aldehydes with substituted acetophenones under alkaline medium (Scheme 47). The cyclization reaction of chalcones with 206 in the presence of glacial acetic acid provided 207.
α-Pyranochalcones 208 and pyrazoline derivatives 210 and 214 were prepared (Warane et al., 2010) to discover chemically diverse anti malarial leads (Schemes 48 and 49). This is the first instance wherein chromeno-pyrazolines have been found to be active antimalarial agents.
3,5-Diaryl pyrazolines analogs 217 were synthesized (Karuppasamy et al., 2010) from the reaction of 215 with hydrazine hydrate and evaluated for their monoamine oxidase (MAO) inhibitory activity (Scheme 50). These compounds were found reversible and selective toward MAO-A with selective index in the magnitude of 103–105.
New pyrazolines derivatives 223 and 224 have been synthesized (Hussain and Sharma, 2010) according to the protocol as given in Scheme 51. In order to introduce methyl group at C-16 instead of C-13, dehydocestus lactone was allowed to react with an ethereal solution of diazoethane.
The synthesis (Sahoo et al., 2010) of novel 3,5-diaryl pyrazolines 226–230 have been investigated in order to study their monoamine oxidase (MAO) inhibitory property (Scheme 52). All the molecules were found to be reversible and selective inhibitor for either one of the isoform (MAO-A or MAO-B).
A series of 1,3,5-trisubstituted pyrazolines 234 were synthesized (Scheme 53) and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (MRC-02) as well as chloroquine resistant (RKL9) strains of Plasmodium falciparum (Achraya et al., 2010). Some of the compounds showed better antimalarial activity than chloroquine against resistant strain of P. falciparum and were also found active in in vivo experiment.
The reaction of pregnenolone 235 with substituted benzaldehydes resulted in the formation (Banday et al., 2010) of the corresponding benzylidine derivatives 236 and finally the reaction of the later with hydrazine hydrate provided pyrazoline 237 as the final product (Scheme 54).
Novel pyrazolines 242 and 245 were synthesized (Chen et al., 2010) from the cyclization of chalcone 240 and 243 with hydrazines 241 and 244 respectively according to the protocol as given in the Scheme 55.
Chalcones 248 were prepared from substituted acetophenones and substituted benzaldehydes (Scheme 56) and condensed with hydrazine hydrate (Venkataraman et al., 2010) in methanol to yield the corresponding pyrazolines 249.
Some new pyrazoline derivatives 254 were synthesized (Ramesh and Sumuna, 2010) by reacting chalcones 252 of 2-acetyl thiophene 250 with phenyl hydrazine hydrochloride in the presence of alcohol and pyridine (Scheme 57).
An efficient method has been established for the synthesis (Kasabe and Kasabe, 2010) of new pyrazoline derivatives 260 which were obtained from the reaction of chalcone 259 with thiosemicarbazide under alkaline alcoholic condition. The intermediate 259 was released from the reaction sequence as shown in Scheme 58.
The synthesis (Gembus et al., 2010) of biologically important 3,4-substituted pyrazolines 263 has been achieved by an organocatalyzed aza-Michael/transimination domino reaction between hydrazones and enones 262 making use of a mixture of heterogeneous resin-bound acid/base reagents (Scheme 59).
A series of new succinyl spacer bis-(3,5-substituted 2-pyrazolines and 1H-pyrazoles) and the non-symmetrical 2-pyrazolines derivatives had been synthesized (Bonacorso et al., 2010). The succinyl substituted bispyrazoles 266 were obtained from the cyclocondensation reactions of 4-substituted 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones 264 (where the 4-substituents are H, Me, Ph, 4-FC6H4, 4-ClC6H4, 4-OMeC6H4, 4-NO2C6H4, 1-naphthyl and 2-furyl) with succinic acid dihydrazide in ethanol as solvent under the controlled reaction conditions (Scheme 60).
The complexes of 2-(8-quinolinol-5-yl)-amino methyl-3(4-methyl phenyl)-5-(phenyl)-pyrazoline 272 with Cu(II), Mn(II) and Zn(II) have been synthesized (Patel et al., 2010) according to the method which is described in Scheme 61.
Recently, B. Vibhute et al. Mokle et al. (2010) have prepared a series of 2-pyrazolines 274 from the cyclization reaction of α,β-unsaturated ketone 273 with hydrazine hydrate/phenyl hydrazine using triethanolamine as the solvent (Scheme 62).
New pyrazolines 278 were synthesized starting from the condensation of substituted aldehydes with substituted acetophenones in the presence of alkali to yield chalcones 277. The resulted chalcones were further reacted with phenyl hydrazine hydrochloride in ethanol and pyridine (Das et al., 2010) to provide 278 as the final products (Scheme 63).
New pyrazolines have been obtained from the condensation of chalcones of 41-piperazine acetophenone with phenyl hydrazine hydrochloride (Rahaman et al., 2010).
The aldol condensation reaction (Nassar, 2010) between 3-indolaldehyde 279 and 4-methoxyacetophenone 280 afforded chalcone derivatives 281 which were further reacted with the cyclizing agents such as hydrazine hydrate and phenyl hydrazine to yield pyrazolines 282 and 281 (Scheme 64).
The heterocyclic compounds 286 have been synthesized (Gupta et al., 2010) starting from the Claisen–Schmidt reaction of aryl methyl ketones 284 and 4-chlorobenzaldehyde 285 to give 286. The reaction of chalcone with phenylhydrazine in glacial acetic acid using ultrasonic irradiation led to the formation of 1,3,5-triphenyl-pyrazolines 287 (Scheme 65).
An efficient and simple procedure has been developed (Azarifar et al., 2010) for the oxidation of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 289 and isoxazoles 289 to their corresponding aromatic derivatives which was promoted by bis-bromine-1,4-diazabicyclo[2.2.2]octane complex (DABCO-Br2) in acetic acid at room temperature (Scheme 66).
1-Benzimidazolyl-3-aryl-prop-2-ene-1-ones 291 have been transformed into N1-substituted pyrazoline derivatives (Rajora et al., 2010) by reacting with phenyl hydrazine, hydrazine hydrate in the presence of formic acid under solvent free microwave induced protocol to give 292 and 293 respectively while the reaction of 291 with thiosemicarbazide under anhyd. K2CO3 could provide 294 (Scheme 67).
The chalcones 297 and 300 were released (Babu et al., 2007) starting from 2-acetyl benzofuran 295 and further condensed with different aromatic acid hydrazides to give the corresponding pyrazolines 298 and 301 (Scheme 68).
Pawan K. Sharma and co-workers (Sharma et al., 2010) have reported the synthesis of new pyrazolylpyrazolines 306. These compounds were obtained by the reaction of appropriate chalcones 304 with 4-hydrazinobenzenesulfonamide hydrochloride in alcoholic medium (Scheme 69).
The pyrazoline compounds 309 and their 1-acetylated derivatives (Congiu et al., 2010), bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings were obtained according to the reaction sequence as shown Scheme 70 and these compounds were also evaluated for antitumor activity. The results of the in vitro assay against a non-small cell lung carcinoma cell line (NCI-H460) showed several compounds to be endowed with cytotoxicity in micromolar to submicromolar range, depending on the substitution pattern and position of aryl rings on 4,5-dihydropyrazole core. Potent and selective activity was also observed in the NCI 60 human cancer cell line panel.
An efficient preparation of compounds 314 has been reported with the objective of discovering the novel (Scheme 71) and potent anti-inflammatory agent (Chandra et al., 2010). The compound 1-(2′,4′-Chloroacridine-9′-yl)-3-(5′-pyridine-4-yl)-(1,3,4-oxadiazol-2-ylthiomethyl)-pyrazole-5-one 314 showed better anti-inflammatory and analgesic activities at the three graded dose of 25, 50 and 100 mg/kg p.o.
A series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazolines 318 were synthesized (Girisha et al., 2010) in one step by condensing suitably substituted propenones 317 with hydrazine in the presence of acetic/propionic acid (Scheme 72).
The reaction of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-2-yl)-acetamide 320 with phenyl isothiocyanate/dimethylsulphate afforded (Gouda et al., 2010) the corresponding ketene N,S-acetal 322 which upon treatment with hydrazine hydrate and 4-aminoantipyrine resulted in the formation of pyrazole derivatives 323 and 324 respectively (Scheme 73).
The treatment (Abu-Surrah et al., 2010) of 5-hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole 325 with substituted benzaldehydes 326 in methanol gave new substituted Schiff base ligands 327 (Scheme 74).
Recently, synthesis and pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 1,5-diarylpyrrole-3-carboxamides 331 have been reported (Gluszok et al., 2010) and these derivatives were prepared by a solid-phase strategy involving a PS(HOBt) resin (Scheme 75).
A series of novel 5-aryl-1-arylthiazolyl-3-ferrocenyl-pyrazoline derivatives 335 have been synthesized (Liu et al., 2010) by the reaction of ferrocenyl chalcone 383 and thiosemicarbazide followed by the reaction with 2-bromo-1-arylethanone in 48–90% yields (Scheme 76).
To find structural requirements for more active antiamoebic agents than metronidazole, the synthesis and comparative QSAR modeling was done on a variety of 1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines 335a (Adhikari et al., 2010). The best model was obtained by using PLS technique with R2A and R2CV value of 88.50% and 82.90%, respectively. Amoebicidal activity may increase when Wang–Ford charges at atom numbers 6 and 12 have large positive values. Number of six-membered ring and sum of Kier–Hall electrotopological states may also increase the amoebicidal activity when these have large positive values. Increasing value of rotatable bond fraction, approximate surface area and mean atomic polarizability scaled on carbon atom may be detrimental for antiamoebic activity. Decrease in values of electrostatic potential charges at atom numbers 1 and 12 may be conducive for activity and the electrophilic attacks may be favorable at these positions.
The reaction of 336 with primary amine leads to the formation of pyrrole (Xue et al., 2010) while similar treatment of 336 with secondary amine provides 337 and 338 (Scheme 77).
A convenient synthesis (Krishna and Prapurna, 2010) of pyrazolines 341 is reported via DABCO mediated reaction of ethyl diazoacetate (EDA) with Baylis–Hillman acetates (Scheme 78). Here the products were obtained in good to excellent yields (70–95%).
A series of N-substituted-3-[(2′hydroxy-4′prenyloxy)-phenyl]-5-phenyl-4,5-dihydro-(1H)-pyrazolines 346 and 347 were synthesized (Scheme 79) and tested on human monoamine oxidase-A and -B isoforms (Fioravanti et al., 2010). The structure activity relationships and molecular modeling showed that some substituents, such as benzyloxy or chlorine, improve the best interaction with active site of hMAO-B.
Iodocyclization of 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyrazolcarboxamides 349 with aromatic aldehydes 350 gave a new series of pyrazolo[3,4-d]pyrimidine derivatives 350 in a single step (Bakavoli et al., 2010) and their antibacterial activity was found to be comparable to Streptomycin which was used as a reference drug (Scheme 80).
Bandgar et al. (2010) have described the synthesis of a combinatorial library of 3,5-diaryl-pyrazole derivatives 352 using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one 351 and hydrazine hydrate in absolute ethanol under the refluxing conditions (Scheme 81).
Recently, a series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides 354 have been synthesized as new ligands of the human recombinant receptor hCB1 (Silvestri et al., 2010). n-alkyl carboxamides brought out different SARs from the branched subgroup (Scheme 82).
The novel 3,4-disubstituted pyrazoles 359 were prepared (Franchini et al., 2010) according to the reaction sequence as shown in Scheme 83.
The functionally substituted pyrazole compounds 364 and 365 have been prepared (Nitulescu et al., 2010) and evaluated in vitro for their antiproliferative effects on a panel of 60 cellular lines, according to the National Cancer Institute screening protocol (Scheme 84). Three of the 12 tested compounds showed moderate antitumor activity, one of them being chosen for the 5-dose assay and presented logGI50 values up to 5.75.
The new compound 3-[(E)-3-(dimethylamino)acryloyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile 369 was prepared (Farag et al., 2010) via the reaction of 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile 366 with dimethylformamid-dimethylacetal (DMF-DMA) (Scheme 85). The heterocyclic compound 374 has been obtained starting from 370 via various steps as shown in Scheme 86.
The novel dipyrazole ethandiamide compound of pyrazolo[3,4-d]pyrimidine 4(5H)-one 377 was synthesized (Youssef et al., 2010) and reacted with a number of nucleophiles to yield 378. These compounds were tested in several in vitro and in vivo assays (Scheme 87). Two compounds were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. Modeling studies by using the molecular operating environment module showed comparable docking scores for the two enantiomers docked in the active site of cyclooxygenase-2.
A series of potential anti-oxidant and anti-bacterial N′-arylmethylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetohydrazides 383 were synthesized (Ahmad et al., 2010) in a facile way starting from commercially available saccharine. The various steps involved in these syntheses are shown in Scheme 88.
Pyrazole carboxylic acid derivatives (Kasimogullari et al., 2010) of 5-amino-1,3,4-thiadiazole-2-sulfonamide (inhibitor 1) 385 were obtained from ethyl 3-(chlorocarbonyl)-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-4-carboxylate compound (Scheme 89).
Regioselective 1,3-dipolar cycloaddition of nitrilimines with 5-arylidene-2-arylimino-4-thiazolidinones and with 2-(4-arylidene)thiazolo[3,2-a]benzimidazol-3(2H)-ones 386 afforded (Abdel-Aziz et al., 2010) the corresponding 1,3,4-triaryl-5-N-arylpyrazole-carboxamides 388 and pyrazolylbenzimidazoles 389 (Scheme 90).
Adam A. Bekhit et al. (2010) have reported the synthesis of a novel series of 4-thiazolylpyrazolyl derivatives 400 according to the reaction sequence as given in Scheme 91. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet-induced granuloma and carrageenan-induced rat paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were also determined.
The heterocyclic compounds (E)-1-aryl-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 405 (pyrazolic chalcones) were synthesized (Insuasty et al., 2010) from a Claisen–Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes 404 with several acetophenone derivatives. Subsequently, the microwave-assisted cyclocondensation reaction of chalcones 405 with hydrazine afforded the new racemic 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 405 a or their N-acetyl derivatives 405 b when the reactions were carried out in DMF or acetic acid, respectively (Scheme 92).
1-(3′-(9H-carbazol-4-yloxy)-2′-hydroxypropyl)-3-aryl-1H-pyrazole-5-carboxylic acid derivatives 408 have been prepared (Nagarapu et al., 2010) by the reaction of ethyl 3-aryl-1H-pyrazole-5-carboxylate 406 with 4-oxiranylmethoxy-9H-carbazole 407 in moderate to excellent yields (Scheme 93). The cytotoxicity of synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against cancer cells such as SK-N-SH human neuroblastoma (NB), human A549 lung carcinoma, human breast cancer MCF-7 cell lines. The results showed that seven compounds can suppress SK-N-SH tumor cancer cell growth.
Two series of pyrazole derivatives 411 and 412 (Lv et al., 2010) designing for potential EGFR kinase inhibitors have been investigated (Scheme 94). Some of them exhibited significant EGFR inhibitory activity. The compound 3-(3,4-dimethylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide 411 (C5) displayed the most potent EGFR inhibitory activity with IC50 of 0.07 lM, which was comparable to the positive control erlotinib.
A number of biologically significant conjugates were synthesized by the combination of chromone-pyrimidine, chromone-indolinone, chromone-pyrazole, indole-pyrimidine, indole-indolinone and indole-pyrazole moieties (Singh et al., 2010) according to the method which is described in Scheme 95.
Recently, Serkos A. Haroutounian et al. (Christodoulou et al., 2010) have investigated the synthesis of a series of novel trisubstituted pyrazole derivatives 421 and these compounds have also been PIFA-mediated converted to molecules bearing the fused pyrazolo[4,3-c]quinoline ring. The various steps involved in these syntheses have been described in Schemes 96.
New 1-N-substituted-3,5-diphenyl-2-pyrazoline derivatives 430 have been synthesized (Scheme 97) and their cyclooxygenase (COX-1 and COX-2) inhibitory activities have also been evaluated (Fioravanti et al., 2010). The results of these biological assays showed that all the new derivatives are not endowed with improved anti-inflammatory activity against COX-1, but some of them showed a good activity against COX-2.
The compounds 439 have been released (Velankar et al., 2010) starting from benzyl nitrile 431 through the multistep reactions and their conditions have been depicted in Scheme 98. The synthesized compounds showed interleukin-2 inducible T-cell kinase (ITK) which is one of the five kinases that belong to the Tec kinase family and it plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma.
The synthesis of a series of pyrazoles 443 has been reported (Scheme 99) and these heterocyclics were also evaluated for their PDE4 inhibitory activity (Biagini et al., 2010). All the pyrazoles were found devoid of activity, whereas some of the pyrazolo[3,4-d]pyridazinones showed good activity as PDE4 inhibitors.
3,5-Diaryl-1H-pyrazoles 446 were prepared (Shaw et al., 2010) from the cyclization of 1,3-diketone 446 with hydrazine hydrochloride (Scheme 100). The major interest in the study was to obtain a molecular template which may act as growth-inhibitory agents.
The cyclization of chalcones 450 with 2-(quinolin-8-yloxy) acetohydrazide 451 under basic condition (Hayat et al., 2010) led to the formation of new pyrazoline derivatives 452 (Scheme 101).
In order to find a new class of antimicrobial agents (Bondock et al., 2010), a series of pyrazole 460 and 462 and other related products 458 containing benzothiazole moiety have been reported by Samir Bondock et al. according to the detailed protocol which is given in Scheme 102.
Novel 1,5-diaryl pyrazole derivatives 466 and 467 were synthesized (Ragavan et al., 2010) from the condensation of 464 with phenyl hydrazine in alcoholic medium (Scheme 103).
An effective and solvent free method for the synthesis (Kumar et al., 2011) of pyrazole-substituted chalcones 470 has been achieved by grinding pyrazole aldehydes 468 and acetophenones 469 in the presence of activated barium hydroxide (C-200). The products of these reactions have been obtained in high yield and within short span of time (Scheme 104).
A series of new 1,3,5-trisubstituted-2-pyrazolines 473 were prepared (Srinath et al., 2011) by reacting chalcones 471 with phenylhydrazine hydrochloride 472 (Scheme 105).
Regioisomeric spiropyrazolines 479 and 480 were synthesized (Dadiboyena and Hamme, 2011) through a tandem intramolecular cyclization/methylation reaction of a functionalized 5,5-disubstituted pyrazoline in one reaction vessel (Scheme 106).
1,3,5-Trisubstituted pyrazolines 481 are rapidly and conveniently oxidized (Azarifar et al., 2011) to their corresponding pyrazoles 483 by 1,3-dichloro-5,5-dimethylhydantoin (DCH) in solution and solvent-free conditions under microwave irradiation (Scheme 107). The presence of silica gel as a supporting agent is shown to be effective in reducing the reaction times and increasing the yields.
The zwitterionic intermediates generated from dialkyl azodicarboxylates and triphenylphosphine displayed excellent reactivity (Papafilippou et al., 2011) toward 3-formylchromones to afford chromeno[2,3-c]pyrazolines 487 and chromeno[2,3-e]tetrazepines 488 (Scheme 108).
A series of 2-pyrazolines 492 have been synthesized (Panta et al., 2011) from α,β unsaturated ketones 491 and hydrazine hydrate with acetic/formic acid in ethanol/DMSO as shown in Scheme 109.
Acknowledgment
Authors are highly thankful to DST (SERC, Fast Track Scheme no. SR/FT/CS-041/2010), New Delhi for providing the financial support for this research work.
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