Editor-in-Chief Hatice Kübra Elçioğlu Vice Editors Levent Kabasakal Esra Tatar Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2012 , Vol 16 , Num 2
The synthesis and biological activities of 3-acyl- 2,3-dihydro-1,3,4-oxadiazole/ 3-acyl-1,3,4-oxadiazoline derivatives obtained from hydrazide-hydrazones
Sevim Rollas, Sevgi Karakuş
Marmara Üniversitesi, Eczacılık Fakültesi, İstanbul, Türkiye DOI : 10.12991/201216410

Summary

Bu derlemede, 3-açil- 2,3-dihidro-1,3,4-oksadiazol türevlerinin sentezi ve biyolojik aktiviteleri sunulmuştur. 1,3,4-Oksadiazolinler'in karboksilik asit hidrazid-hidrazonlarından hareketle asetik anhidrit veya diğer siklizasyon ajanları kullanılarak yapılan sentez çalışmaları derlememizin temelini oluşturmaktadır.

Introduction

The hydrazide-hydrazones are obtained from the condensation of hydrazides and aldehyde or ketones[1-5]. Also, unsubstituted or monosubstituted hydrazones are converted into hydrazide-hydrazones with acylated agents[1]. Being one of the most important raw material, hydrazide-hydrazones and hydrazones have been used in the various chemical synthesis[1,6-10]. The acyl- and aroylhydrazones are very important as chelating agents[11-14] Compounds containing hydrazide and hydrazone moiety proved to be especially attractive due to their application in biology[4,15-21] and medicine, isocarboxazide, iproniazide, isoniazid, nifuroxazide, rifampisin as example drugs. Also hydrazones are the most important compounds for prodrug design due to their poor metabolic stability[1,22-24]. The plasma stability of the prodrugs is very important for rapid conversion in plasma[25]. The formation of hydrazone is an suitable reaction for prodrug synthesis[26-30]. They are easily hydrolyzed to active drugs in vivo. Hydrazide-hydrazones have also been employed for the preparation of the heterocyclic compounds such as 4-thiazolidinone[31,32], azetidinone[33,34], 1,3,4-oxadiazole and 2,3-dihydro- 1,3,4-oxadiazol rings. The substituted 1,3,4-oxadiazole derivatives have been obtained from hydrazide-hydrazones by the oxidative cyclization[35-37]. The hydrazone functional group is usually not stable in vivo[22,38] and in vitro[23,39]. However the hydrolytic stability of hydrazones are depend on the structure of the substituent[1]. 2,3-Dihydro- 1,3,4-oxadiazol derivatives are stable structures[40] and obtained from intramoleculer cyclization of hydrazide hydrazones by acid anhydrides or acylchlorides[1,41-46]. In 1953, Yale and co-workers[41] reported the publication of related compounds. In 2002, Rollas and co-workers[45] demonstrated that some hydrazones of 4-fluorobenzoic acid hydrazide and their 1,3,4-oxadiazoline derivatives showed antibacterial and antifungal activities. The monoamine oxidase inhibitory activities of 3-acetyl-1,3,4-oxadiazolines were investigated by Maccioni and co-workers[47]. The most detailed researches have been made by Somogyi and co-workers[42,48-51].

There are only a few reports on 3-acetyl-1,3,4- oxadiazolines which obtained from hydrazide-hydrazones with acetic anhydride and the other cyclization agents. Purpose of this review is to summarize synthetic approaches and report the biological activities of 3-acyl-2,3-dihydro-1,3,4-oxadiazol derivatives. The literature covers through 1953.

SYNTHESIS OF 3-ACYL-2,3-DIHYDRO-1,3,4- OXADIAZOLE DERIVATIVES
Cyclizaton of hydrazide-hydrazones Acetyl derivatives
The 3-acetyl-2,3-dihydro-1,3,4-oxadiazole derivatives have been obtained via acetylation and intramolecular cyclation of hydrazide-hydrazones using acetic anhydride. The 3-acetyl- 1,3,4-oxadiazolines 1[41], 2[43], 3[44,52], 4[53], 5[54], 6[55], 7[56], 8[579 and 9[58], 10[59], 11[60] and 12[61] were synthesized by the cylization of the corresponding hydrazide-hydrazone derivatives in acetic anhydride. The reaction time, temperature, and yields have been shown slightly different.

In the other variations of this method, anhydrous sodium acetate[62] has been added in the reaction medium besides acetic anhydride. Also, the 1,3,4-oxadiazolines were synthesized from the corresponding hydrazide-hydrazones in acetyl chloride[48,63,64].

On the other hand, the spiro 1,3,4-oxadiazolines were obtained from the reaction acetic anhydride 14[65] 17, 18, 19, 20[66] or acetic acid 22[67] on cyclic ketone–hydrazone derivatives.

The compounds were obtained with (R)- and (S)- configurations at C-3[66]. Wang and co-workers[67] isolated also the E and Z isomer of some hydrazide hydrazones and from these isomers synthesized the S and R isomers of spiro1,3,4-oxadiazoline derivatives.

The cyclization of 21 was carried out in acetic acid by Allam and co-workers[68] and obtained nonacetylated spiro1,3,4- oxadiazoline derivative 22.

The dehydrogenation of 3-acetyl-2,3-dihydro-1,3,4-oxadiazoles 24 with potassium permanganate has been given substituted 1,3,4-oxadiazoles 25[51]

Similarly, the 3-acetyl-2,3-dihydro-1,3,4-thiadiazole derivatives 27[69] are obtained from thiosemicarbazones. When the cylic ketone is used, the spiro 1,3,4-thiadiazolines 29 have been formed[70].

Other acyl derivatives
The intramoleculer cyclization of hydrazide hydrazones have also been carried out with propionic anhydride 31[40], benzoyl chloride 32[48], 33[63] and substituted isocyanates 35, 36[71,72].

The isomer compounds 38 and 39 were synthesized with the different method by Tsoleridis and co-workers[73].

Desai and co-workers[74] synthesized 3-(substituted-phenylpropenoil)-1,3,4-oxadiazoline derivatives 41 from 3-acetyl-2-(2-chloroquinolin- 3-yl)-5-(4-nitrophenyl)-1,3,4-oxadiazoline 40.

Different methods for the synthesis of 1,3,4-oxadiazolines
The regioselective cyclization of 1,4-disubstituted thiosemicarbazides has been shown to be a good method for the synthesis of substituted 1,2,4-triazoles[75,76] and 1,3,4-thiadiazoles[77,78] in alkaline and acidic media respectively. Feng and co-workers[79] published the first report on the regioselective cyclization of 1,3,4-oxadiazolines from 1,4-disubstituted thiosemicarbazides using silver nitrate as an oxidant. The products have isolated as the trans-isomer.

El-Saidi and co-workers[80] prepared the Δ3-1,3,4-oxadizoline derivatives 45 by oxidative cylization of compound 44 using the different starting compound with lead tetraacetate in alcohol.

Also, El-Kaim and co-workers[81] synthesized the Δ3-1,3,4- oxadiazolines 47 from trichloroacetic acid hydrazones 46.

Biological Activity
The investigation of the biological activities of 3-acyl-2,3-dihydro- 1,3,4-oxadiazole derivatives has been focused on antibacterial, antitumor, antioxidant, monoamine oxidase inhibitory and anticonvulsant activity.

Rollas and co-workers[45] synthesized 4-fluorobenzoic acid[(4-nitrophenyl/5-nitro-2-furanyl)methylene]hydrazide derivatives and tested against various bacteria and fungus. Compound 48 showed equal activity with ceftriaxone against S.aureus.

Also, Fuloria and co-workers[82] screened the compounds 49a-e for their antibacterial and antifungal activity against S. aureus, P. aeruginosa, C. albicans and A. flavus. Compounds were found to be active against tested microorganism.

50a and 50b were tested for their antitubercular activity against M. tuberculosis H37Rv strain. Compounds showed moderate activity (MIC: 31.25, Isoniazid: 0.25 μg/mL)[83].

The cylization of the pyridoxalisonicotinoyl hydrazone with acetic anhydride gave 51. Compound 51 exhibited inhibitory activity against M. tuberculosis H37Rv (MIC, 6.09 μM)[84].

Chawla and co-workers[85] synthesized a series of 3-acetyl-5- (3-chloro-1-benzo[b]thiophen-2-yl)-2-substitutedphenyl-2,3- dihydro-1,3,4-oxadiazoles. Among the tested compounds 52a and 52b were found to be most active compounds compare to standart drug ciprofloxacin against S. aureus and B. subtilis.

Yang and co-workers[86] synthesized 3-(substituted)aryl-4- (acetyl-2-aroyloxymethylene-1,3,4-oxadiazoline-5-yl)-1-phenyl- 2-pyrazoline derivatives 53. Their antibacterial activities were found higher than the initial hydrazide-hydrazones against tested microorganisms.

In a recent publication, Hamdi and co-workers[87] have investigated 1,3,4-oxadiazoline derivatives for their antibacterial and antioxidant activities.

Generally, the antibacterial activities of 1,3,4-oxadiazoline derivatives screened against S. aureus. Indeed, all of the researchs showed that 1,3,4-oxadiazolines were active compounds.

Also, Ishii and co-workers[88] synthesized the 1,3,4-oxadiazolines and tested for their antimicrobial activities against various strains. The most active compounds were 55a-c. Compound 55b showed good activity against S. aureus (MIC=1.95-1.25 μg/mL) and 55a against C. albicans (MIC=3.28-2.62 μg/mL).

Omar M. Ali and co-workers[89] synthesized 1,3,4-oxadiazoline derivatives 56 from sugar uracil-1-ylmethylhydrazones by heating in acetic anhydride. Compounds were tested for antiviral activity against hepatitis B virus and showed moderate viral replication inhibition.

Compounds 57a-c were tested for antimicrobial activities various strains. The compounds did not show remarkable activity[90].

Manojkumar and co-workers[91] prepared 3-acetyl-1,3,4-oxadiazolines 58a-c using starting material 4-methoxycoumarinyl-7- oxyacetic acid hydrazide hydrazones.

The compounds 58a-c have tested for their in vitro cytotoxic activity against DLH and EAC cells. 5-Fluorouracil was used as standart cytotoxic agent. In addition, their antioxidant activities have studied by diphenylpicryl hydrazyl (DPPH) assay method.

Also Jin and co-workers[92] reported that compound 59 was active against PC3 cells in vitro by MTT method at 0.3 μM.

Lee and co-workers[93] prepared 2,5-diaryl-1,3,4-oxadiazoline analogs 59 of combretastatin A4 and tested antiproliferative activities against multiple cancer cell lines and reported that it was the major efficient antioxidant bearing 3,4,5-trimethoxysubstituent in the phenyl ring. Other compounds have also exhibited higher antioxidant activity than Trolox.

Ke and co-workers[72] designed and synthesized a series of oxadiazoline derivatives. All synthesized compounds have inhibited chitin biosynthesis in yeast. Compounds 60 and 61 have showed the highest inhibitory activity at lower concentrations.

In 2005, Chimenti and co-workers[94] reported the synthesis of 1-acetyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives and their human monoamine oxidase activity against (MAO) A and B isoforms.

Recently, Maccioni and co-workers[47] designed and synthesized 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazole derivatives as isosteres of 1-acetyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazoles to investigate for their inhibitors activity against MAO-A and MAO-B. Some of the compounds 62 exhibited inhibitory activities against the B isoform of the enzyme at nanomolar values. The authors isolated R and S enantiomers of 62b and 62c. The R enantiomers were found more active than the racemic mixture. These lead compounds may be used for the design of MAO-B selective inhibitors.

The hydrazones derivatived 3-hydroxy-2-naphthoic acid hydrazide gave compounds 63. Their anticonvulsant activity were investigated against pentylenetetrazole (PTZ) induced convulsions in mice by Doğan and co-workers[95].

The protection of these compounds was ranged from 0 to 60%. Further research was made on the compound 64 by Şener and co-workers[96].

The antioxidant effect of compound 64 was tested in mice brain and liver, compared the antioxidant and anticonvulsive effect with that of valproat (VPA), an antiepileptic drug. Compound 64 and VPA significantly decreased lipid peroxidation levels in brain and liver which were elevated after PTZ administration. Compound 64 and VPA showed a protection on brain and liver tissue against oxidative damage seen at during the seizures.

On the other hand, nonsubstituted analogs of 63, 64 were evaluated for biological activities as tubulin polymerization inhibitors by Hu and co-workers[97].

Among these compounds 65 showed the most potent antiproliferative activitiy against HepG2, MFC-7 and B16-F10 cells. Docking simulation study revealed that compounds bearing the naphthyl moiety are promising tubulin inhibitors.

The 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles were prepared from aryl substituted hydrazones of 4-fluoro benzoic acid hydrazide by Koçyiğit-Kaymakçıoğlu and coworkers[98]. 66 can be interesting source for lead compounds for anti-inflammatory research.

Conclusion

The number of publications on the 3-acyl-2,3-dihydro-1,3,4- oxadiazole derivatives have increased in the recent years. There are several reports about the synthesis and biological activity of 3-acyl-2,3-dihydro-1,3,4-oxadiazoles. In this manuscript the related articles of 1,3,4-oxadiazolines are reviewed. The future researches may be focused on the 1,3,4-oxadiazolines for the synthesis of active new drugs.

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