Synthesis and Pharmacological Evaluation of Fenamate Analogues: 1,3,4-Oxadiazol-2-ones and 1,3,4-Oxadiazole-2-thiones

Abstract

A series of fenamate pyridyl or quinolinyl analogues of 1,3,4-oxadiazol-2-ones 5a-d and 6a-r, and 1,3,4-oxadiazole-2-thiones 5e-g and 6s-v, respectively, have been synthesized and evaluated for their analgesic (hot-plate) , antiinflammatory (carrageenin induced rat's paw edema) and ulcerogenic effects as well as plasma prostaglandin E2 (PGE2) level. The highest analgesic activity was achieved with compound 5a (0.5 ,0.6 ,0.7 mrnolkg b.wt.) in respect with mefenamic acid (0.4 mmollkg b.wt.). Compounds 6h, 6l and 5g showed 93, 88 and 84% inhibition, respectively on the carrageenan-induced rat's paw edema at dose level of 0.1rnrnol/kg b.wt, compared with 58% inhibition of mefenamic acid (0.2mmoll kg b.wt.). Moreover, the highest inhibitory activity on plasma PGE2 level was displayed also with 6h, 6l and 5g (71, 70,68.5% respectively, 0.lmmolkg b.wt.) compared with indomethacin (60%, 0.01 mmolkg b.wt.) as a reference drug. In addition 6i, 6k, 6p, 6r, 6t and 6v were devoid of any ulcerogenicity.

Discovery of AZD6642, an Inhibitor of 5-Lipoxygenase Activating Protein (FLAP) for the Treatment of Inflammatory Diseases

“…In addition, substituted heteroaromatic rings were well tolerated, exemplified here with two oxadiazoles (20,21). In summary, both acidic and basic moieties as well as neutral groups with hydrogen bond donors or acceptors in R 2 could lead to potent inhibitors.…”

Synthesis, Analgesic and Anti-inflammatory Activities of Some New Fenamate Analogues

“…Thus, several ideas were attempted to ameliorate the undesirable effects of the acidic group. One approach was to convert it to an ester, carbohydrazide or arylidene derivative [11].…”

“…Another approach was to incorporate the carboxyl function in another less acidic heterocyclic biologic isosteres e. g. 1,3,4-oxadiazol-2-thione [12]. These changes provided dual inhibition of cyclooxygenase and 5-lipooxygenase enzymes [11][12][13][14].…”

Anti-HIV Activity of New Substituted 1,3,4-Oxadiazole Derivatives and their Acyclic Nucleoside Analogues

“…Among the fi ve-membered nitrogen heterocycles, 1,3,4-oxadiazoles are associated with a broad spectrum of biological activities (Zareen et al, 2004;El-Azzouny et al, 2003;Loetchutinat et al, 2003). Their derivatives possess antibacterial (Ates et al, 1997), antimicrobial (Rahman and Farghaly, 2004), insecticidal (Li et al, 2003), herbicidal, fungicidal (Zou et al, 2002), anti-infl ammatory (Palaska et al, 2002), and hypoglycaemic (Mhasalkar et al, 1971) characteristics, and antiviral (El-Emam et al, 2004) and antitumour activities (Liszkiewicz et al, 2003).…”