Abstract:A series of 20 novel benzimidazole and benzothiazole derivatives linked to a 1,2,3-triazole ring system was synthesised, characterised and evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity. Several copper catalysts and solvents were screened to establish the optimal conditions for the preparation of the target compounds. Three different linkers were used to optimise the enzyme inhibitory effect. Out of the 20 compounds, 13 showed some AChE inhibition. The most potent compound, which showed… Show more
“…To a solution mixture of 3 mmol of 2 and 4 mmol of aldehyde (3)(4)(5) in ethanol (3 mL), 6 mmol of sodium bisulfite were added under stirring. The reaction mixture was heated at 80 • C under reflux for 24 h. The solvent was then evaporated under vacuum and the solid was treated with HCl 2N.…”
Section: Synthesis Of 2-substituted Benzimidazole-5-sulfonic Acidsmentioning
confidence: 99%
“…Heterocyclic compounds are fundamental building blocks of various essential natural and synthetic compounds. They play an important role in drug design thanks to their ability to act as both biomimetic and reactive pharmacophores [4]. Many of them are five-and / or six-membered heterocyclic compounds having one to three heteroatoms (especially oxygen, nitrogen and sulfur) in their structure and are significant in organic chemistry, medicinal chemistry and biochemistry [5].…”
In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or –SO3H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10, bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.
“…To a solution mixture of 3 mmol of 2 and 4 mmol of aldehyde (3)(4)(5) in ethanol (3 mL), 6 mmol of sodium bisulfite were added under stirring. The reaction mixture was heated at 80 • C under reflux for 24 h. The solvent was then evaporated under vacuum and the solid was treated with HCl 2N.…”
Section: Synthesis Of 2-substituted Benzimidazole-5-sulfonic Acidsmentioning
confidence: 99%
“…Heterocyclic compounds are fundamental building blocks of various essential natural and synthetic compounds. They play an important role in drug design thanks to their ability to act as both biomimetic and reactive pharmacophores [4]. Many of them are five-and / or six-membered heterocyclic compounds having one to three heteroatoms (especially oxygen, nitrogen and sulfur) in their structure and are significant in organic chemistry, medicinal chemistry and biochemistry [5].…”
In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or –SO3H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10, bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.
“…First, the thiol functionality in the 2-position of compound 1 was regioselectively alkylated with propargyl bromide in the presence of triethylamine as a basic catalyst in refluxing ethanol for 1 h to afford target thiopropargylated benzimidazole 2 in 94% yield (Scheme 1). It should be noted that the regioselective synthesis of the thiopropargylated benzimidazole 2 has been previously described using different reaction conditions (NaOH/H 2 O, K 2 CO 3 , H 2 O) [50–52]. Scheme 1Synthesis of thiopropargylated benzimidazole 2 Scheme 2Synthesis of mono-1,4-disubstituted-1,2,3-triazole tethered benzimidazole-sulfonamide conjugates 5a – f Scheme 3Synthesis of S,N -Bispropargylated benzimidazole 5 Scheme 4Synthesis of S,N -bis(1,2,3-triazole-sulfonamide)-benzimidazole hybrids 6a – f …”
Section: Resultsmentioning
confidence: 99%
“…To a solution of 2-mercaptobenzimidazole ( 1 ) (10 mmol) in ethanol (40 mL) and triethylamine (Et 3 N) (12 mmol) was added propargyl bromide (12 mmol) with stirring, and the solution was heated to reflux for 1 h. The excess solvent was removed under reduced pressure, and the resulting crude product was washed with water and recrystallized from ethanol to afford compound 2 in 94% yield as colourless crystals, mp: 163–164 °C (lit. 164–165 °C [50, 51]); IR (KBr) υ max /cm −1 1580 (C=C), 1615 (C=N), 2140 (C≡C), 2950 (C–H al), 3070 (C–H Ar), 3310 cm −1 (≡CH), 3390 cm −1 (N–H). 1 H NMR (400 MHz, DMSO- d 6 ) δ H = 3.20 (s, 1H, ≡CH), 4.16 (s, 2H, SCH 2 ), 7.14–7.16 (m, 2H, Ar–H), 7.46–7.51 (m, 2H, Ar–H), 12.65 (s, 1H, NH).…”
BackgroundNitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers.ResultsA series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a–f and 6a–f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (Et3N and/or K2CO3) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a–f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a–f and 6a–f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC50 values in the micromolar range (55–106 μM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic.ConclusionIn summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 μg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC50 values in the micromolar range (55–106 μM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski’s rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic.
Novel benzazole derivative compounds 4a–4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, 1H-NMR, 13C-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro-phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5-HT1A antagonist), ketanserin (a 5-HT2A/2C antagonist), and ondansetron (a 5-HT3 antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT1A, 5-HT2A/2C and 5-HT3 receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific.
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