Synthesis and biological evaluation of some 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrimidin-2-ones/thiones as potent anti-inflammatory agents

Abstract

Among the wide range of heterocycles explored to develop pharmaceutically important molecules, pyrimidine has played an important role in medicinal chemistry. A survey of literature has shown that compounds having a pyrimidine nucleus possess a broad range of biological activities such as anticancer (1), antiviral (2), antibacterial (3), antimalarial (4), antihypertensive (5) and anti-inflammmatory activities (6, 7). Moreover, chemistry and synthesis of 1,2,3,4-tetrahydropyrimidin-2-ones/thiones have been attracting extensive attention. The importance of these tetrahydropyrimidines is mainly due to their close structural relationship to the clinically important dihydropyrimidine Twelve new 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrimidin-2-ones/thiones (7-18) have been synthesized by reacting 1-aryl-3-(1H-indol-3-yl)-2-propen-1-one with urea and thiourea in ethanolic potassium hydroxide. Their structures have been confirmed by IR, 1 H NMR and mass spectral data. The compounds were tested for their anti-inflammatory activity. Test results revealed that compounds showed 49.5 to 70.7% anti-inflammatory activity whereas the standard drug ibuprofen showed 86.4% activity at the same oral dose. Four compounds, 4-(1H-indol-3-yl)-6-(4-chlorophenyl)-1,2,3,4-tetrahydropyrimidin-2-one (8), 4-(1H-indol-3-yl)-6-(4-methylphenyl)-1,2,3,4-tetrahydropyrimidin-2-one (10), 4-(1H-indol-3-yl)-6-(4-chlorophenyl)-1,2,3,4-tetrahydropyrimidin-2-thione (14), 4-(1H-indol--3-yl)-6-(4-methylphenyl)-1,2,3,4-tetrahydropyrimidin-2-thione (16), that showed significant anti-inflammatory activity were selected to study their ulcerogenic and lipid peroxidation activities. All tested compounds showed significant reduction in the ulcerogenic potential and lipid peroxidation compared to the standard drug ibuprofen.

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

“…Scheme 1 illustrates the synthetic route for the preparation of target compounds. 1-(Substituted phenyl)-3-(1H-indol-3-yl)-2-propen-1-ones 1a-d were prepared by the method reported in literature (Amir et al, 2008). 3-[3-(Substituted phenyl)-4,5-dihydroisoxazol-5-yl]-1H-indoles 2a-d were obtained by cyclization of 1a-d by treating with hydroxylamine hydrochloride in the presence of NaOH in absolute ethanol.…”

“…1), are used clinically for the treatment of different anti-inflammatory disorders and are known to induce erosions and ulcers in the gastrointestinal tract (Hardman and Limbird, 2001;Moore et al, 1996;Yoshikawa et al, 1993). Indole derivatives have been reported to possess a wide variety of biological properties viz., anti-inflammatory (Amir and Kumar, 2005;Amir et al, 2008;Singh et al, 2008), analgesic (Radwan et al, 2007), anticonvulsant (El-Gendy et al, 2008), and antibacterial (Gurkok et al, 2009;Yamamoto and Kurazono, 2007). Furthermore, substitution of heterocyclic moiety at 3-position of indole ring has been shown to improve anti-inflammatory activity (Radwan et al, 2007;Rani et al, 2004).…”

Synthesis and potential biological activity of some novel 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles and 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles

“…The structure of compounds 3a-g and 4a-g was supported by their precise elemental analyses (Table I) and spectral data (Table II). As an example, the IR spectrum of compound 4b showed absorption bands at 3291 (NH 2 formation of new 3,6-diamino-4-(N-substituted-indol-3-yl) pyrano(2,3-c)pyrazole-5-carbonitriles (7a-g) (method A) with the overall yield of 40-68 %. Moreover, compounds 7a-g could also be obtained with an overall yield of 20-47 % via the condensation reaction of N-substituted indole-3-carboxaldehyde (1a-g) with malononitrile to give N-substituted indolylidene malononitriles (5a-g), which reacted with 3-amino-5-pyrazolone in refluxing absolute ethanol containing triethylamine (method B) (Scheme 2).…”

Synthesis and biological evaluation of some novel pyrazolopyrimidines incorporating a benzothiazole ring system

“…Mucosal damage was examined by means of a magnifying glass. For each stomach, the mucosal damage was assessed according to the following scoring system: 0.5 redness; 1.0 spot ulcers; 1.5 hemorrhagic streaks; 2.0 ulcers > 3 but £ 5; 3.0 ulcers > 5 (20). The mean score of each treated group minus the mean score of the control group was regarded as the severity index of gastric mucosal damage.…”