Original article
Condensed bridgehead nitrogen heterocyclic system: Synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid

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Abstract

Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.

Graphical abstract

A series of 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid have been synthesized and evaluated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation and antimicrobial activities.

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Introduction

Currently available non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, flurbiprofen, fenbufen and naproxen exhibit gastric toxicity. Long-term use of these drugs has been associated with gastro-intestinal (GI) ulceration, bleeding and nephrotoxicity [1]. The GI damage from NSAIDs is generally attributed to two factors, i.e. local irritation by the carboxylic acid moiety common to most NSAIDs (topical effect); and decreased tissue prostaglandin production, which undermines the physiological role of cytoprotective prostaglandins in maintaining GI health and homeostasis [2], [3]. The pharmacological activity of NSAIDs is related to the suppression of prostaglandin biosynthesis from arachidonic acid by inhibiting cyclooxygenases (COXs) [2], [4]. The chronic use of NSAIDs including ibuprofen may elicit appreciable GI toxicity [5]. Therefore synthetic approaches based upon chemical modification of NSAIDs have been taken with the aim of improving their safety profile.

Heterocycles bearing a symmetrical triazole or 1,3,4-thiadiazole moieties, represent an interesting class of compounds possessing a wide spectrum of biological activities such as anti-inflammatory [6], [7], [8], antiviral [9] and antimicrobial [10], [11] properties. It has also been reported that derivatives of 1,2,4-triazole and 1,3,4-thiadiazole condensed nucleus systems exert diverse pharmacological activities such as anti-inflammatory [12], antitumor [13], antifungal and antibacterial [14]. Furthermore, literature survey revealed that modification of the carboxyl function of representative NSAIDs resulted in increased anti-inflammatory activity with reduced ulcerogenic effect [15], [16], [17]. Our former studies [18], [19] have shown that certain compounds bearing 1,2,4-triazole and 1,3,4-thiadiazole nuclei possess significant anti-inflammatory activity with reduced GI toxicity. It was therefore considered worthwhile to replace the carboxylic acid group of 2-(4-isobutylphenyl)propanoic acid and biphenyl-4-yloxy acetic acid by a composite system, which combines both the triazole and the thiadiazole nucleus in a ring to give a compact and planar structure. The compounds thus synthesized have been found to possess an interesting profile of anti-inflammatory activity with significant reduction in their ulcerogenic effect. In view of the reported antimicrobial activity of triazolo-thiadiazoles, these compounds were also tested for their antibacterial and antifungal activities. Two selected compounds were also studied for their hepatotoxic effects on rat liver.

Section snippets

Chemistry

The acid hydrazides (1a,b) were prepared by esterification of 2-(4-isobutylphenyl)propanoic acid and biphenyl-4-yloxy acetic acid followed by treatment with hydrazine hydrate in absolute ethanol [18]. 4-Amino-3-substituted-5-mercapto-(4H)-1,2,4-triazoles (3a,b) were prepared following the procedure of Reid and Heindel [20]. The acid hydrazides were allowed to react with carbon disulphide in the presence of potassium hydroxide in ethanol to afford the corresponding intermediate potassium

Anti-inflammatory activity

The anti-inflammatory activity of the synthesized compounds 4ae, 5a,b,df, 6ad and 7a,cd was evaluated by carrageenan-induced paw edema method of Winter et al. [21]. The compounds (4ae, 6ad) were tested at an equimolar oral dose relative to 70 mg/kg ibuprofen and the compounds (5a,b,df and 7a,c,d) were tested at an equimolar oral dose relative to 10 mg/kg flurbiprofen. The tested compounds showed anti-inflammatory activity ranging from 18.17% to 80.29%, whereas standard drugs ibuprofen and

Conclusions

Various triazolo-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid were synthesized and screened for anti-inflammatory, analgesic, ulcerogenic and antimicrobial activities. It was interesting to note that seven cyclised compounds 4c,d, 5b,f, 6a,b and 7c were found to have anti-inflammatory properties comparable to their standard reference drugs ibuprofen and flurbiprofen. When these compounds were subjected to analgesic activity by tail immersion method in mice, all

Experimental protocols

The melting points were determined in open capillary tubes in a Hicon melting point apparatus and are uncorrected. Elemental analysis (C, H, N, S) was performed on the CHNS Elementar (Analysen systime, GmbH) Germany Vario EL III. FTIR spectra were recorded as KBr pellets on a Jasco FT/IR 410 spectrometer and frequency was expressed in cm−1. 1H NMR spectra were recorded on a Bruker model DPX 300 NMR spectrometer. Chemical shifts (δ) are expressed in parts per million relative to

Acknowledgements

The authors are thankful to Head, Department of Pharmaceutical Chemistry for providing laboratory facilities, Central Drug Research Institute (CDRI) for spectral analysis of the compounds, and Majeedia Hospital, Hamdard University for providing necessary strains of bacteria and fungus. Authors are also thankful to Mrs. Shaukat Shah, in-charge animal house, Hamdard University for providing Wistar rats, and Dr. A. Mukherjee, MD, Department of Pathology, All India Institute of Medical Sciences

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