Synthesis and Anti-inflammatory Activities of Novel 5-(3,4-dichlorophenyl)-3-[(4-substitutedpiperazin-1-yl)methyl]-1,3,4-oxadiaxole-2(3H)-thiones

Abstract

Purpose:

To synthesize a new series of 5-(3,4-dichlorophenyl)-3-[(4-substitutedpiperazin-1-yl)methyl]-1,3,4-oxadiaxole-2-thiones for their anti-inflammatory activity.

Methods:

The title compounds synthesized by Mannich reaction of prepared 5-(3,4-dichloro­phenyl)-1,3,4-oxadiazole-2-thione and appropriate substituted piperazine derivatives. The structures of the compounds were confirmed by IR, NMR and elemental analyses. The newly synthesized compounds were evaluated for their anti-inflammatory and ulcerogenic activities.

Results:

Most of the compounds were found to have significant anti-inflammatory profile in carrageenan footpad edema test. The compounds showed anti-inflammatory activity ranging from 30.6% to 57.8% inhibition.

Conclusion:

The compounds 5b, 5f, 5i, 5p and 5r showed most prominent anti-inflammatory activity with low gastric ulceration incidence than the reference drug indomethacine. These compounds could serve as lead molecules for further modifications.

Key words

anti-inflammatory drugs - 1,3,4-oxadiazole-2-thiones - gastric ulceration - piperazine

• References

• 1 Sorbera LA, Lesson PA, Castanar J et al. Valdecoxib and Parecoxib sodium. Analgesic, antiarthritic, cyclooxygenase-2 inhibitor. Drug Future 2001; 26: 133-140
• 2 Palomer LA, Cabre F, Pascual J et al. Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models. J Med Chem 2002; 45: 1402-1411
• 3 Vonkeman HE, Van de Laar MAFJ. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum 2010; 39: 294-312
• 4 Allison ME, Howatson AG, Torrance CJ et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327: 749-754
• 5 Bjarnason I, Hayllar J, MacPherson AJ et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832-1847
• 6 Lanza FL. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol 1998; 93: 2037-2046
• 7 Kalgutkar AS, Marnett AB, Crews BC et al. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem 2000; 43: 2860-2870
• 8 Palaska E, Sahin G, Kelicen P et al. Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones. Il Farmaco 2002; 57: 101-107
• 9 Amir M, Shikha K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino) phenyl]acetic acid derivatives. Eur J Med Chem 2004; 39: 535-545
• 10 Bhandari SV, Bothara KG, Raut MK et al. Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg Med Chem 2008; 16: 1822-1831
• 11 Akhter M, Husain A, Azad B et al. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur J Med Chem 2009; 44: 2372-2378
• 12 Husain A, Ahmad A, Alam MM et al. Fenbufen based 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones as safer antiinflammatory and analgesic agents. Eur J Med Chem 2009; 44: 3798-3804
• 13 Manjunatha K, Poojary B, Lobo PL et al. Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. Eur J Med Chem 2010; 45: 5225-5233
• 14 Kumar H, Javed SA, Khan SA et al. 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: Synthesis and preliminary evaluation of biological properties. Eur J Med Chem 2008; 43: 2688-2698
• 15 Gokulan PD, Jayakar B, Alagarsamy V et al. Synthesis and pharmacological Investigation of 5-substitutd-3-methylsufanyl-1H-pyrazole-4-carboxylic acid esters as new analgesic and anti-inflammatory agents. Arzneimittelforsch Drug Res 2012; 62: 457-462
• 16 Tozkoparan B, Kupeli E, Yesilada E et al. Preparation of 5-aryl-3-alkylthio-1,2,4-triazoles and corresponding sulfones with anti-inflammatory-analgesic activity. Bioorg Med Chem 2007; 15: 1808-1814
• 17 Schenone S, Brullo C, Bruno O et al. New 1,3,4-thiadiazoles endowed with analgesic and anti-inflammatory activities. Bioorg Med Chem 2006; 14: 1698-1705
• 18 Sondhi SM, Dinodia M, Jain S et al. Synthesis of biologically active N-methyl derivatives of amidines and cyclized five-membered products of amidines with oxalyl chloride. Eur J Med Chem 2008; 43: 2824-2830
• 19 Narayana B, Vijayaraj KK, Ashalatha BV et al. Synthesis of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents. Arch Pharm 2005; 338: 373-377
• 20 Akhter M, Akhter N, Alam MM et al. Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity. J Enzyme Inhib Med Chem 2011; 26: 767-776
• 21 Koksal M, Gokhan-Kelekci N, Mercanoglu GO et al. Synthesis and evaluation of analgesic, anti-inflammatory and antioxidant activities of new 6-acyl-3-alkyl-5-methyl-2(3H)-benzoxazolones. ArzneimForsch Drug Res 2008; 58: 398-404
• 22 Koksal M, Bilge SS, Bozkurt A et al. Synthesis, characterization and anti-inflammatory activity of new 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiaxoles. ArzneimForsch/Drug Res 2008; 58: 510-514
• 23 Gokhan-Kelekci N, Koksal M, Unuvar S et al. Synthesis and characterization of some new 2(3H)-benzoxazolones with analgesic and antiinflammatory activities. J Enzyme Inhib Med Chem 2009; 24: 29-37
• 24 Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rats as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 1962; 111: 544-552