Serdar Ülker

Microwave-assisted synthesis of new benzimidazole derivatives with lipase inhibition activity

Abstract A practical protocol has been used for the synthesis of benzimidazoles. The reaction of iminoester hydrochlorides of phenylacetic with 4,5-dichloro-1,2-phenylenediamine under microwave irradiation leads to the benzimidazole derivatives with good yields and in short reaction times. After the synthesis of benzimidazoles, we synthesized ester and hydrazide derivatives under microwave irradiation with good yields. All compounds were evaluated with regard to pancreatic lipase activity and 3b, 3c, 5a and 6a showed lipase inhibition at various concentrations.

Microwave-Assisted Synthesis and Biological Evaluation of Some Benzimidazole Derivatives Containing a 1,2,4-Triazol Ring

A new series of 2‐(4‐(trifluoromethyl)phenyl)‐1H‐benzo[d]imidazole derivatives containing a 1,2,4‐triazole ring were synthesized via microwave technique. This efficient procedure provides pure products within a few minutes. The newly synthesized compounds were confirmed by 1H NMR and 13C NMR spectra and they were screened for their lipase inhibition and antioxidant activities. Compounds 4a, 4b, 5a, and 5b showed very good scavenging activity.

Synthesis of Some New 1,2,4‐Triazole Derivatives Starting from 3‐(4‐Chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol with Anti‐Lipase and Anti‐Urease Activities

In the present study, starting compound 4 was prepared by deamination of compound 2 in the presence of hypophosphorous acid and sodium nitrite. Treatment of compound 4 with ethyl bromoacetate produced ethyl[3‐(4‐chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol‐4‐yl]acetate (5), which was converted to the hydrazide derivative (6) by treatment with hydrazine hydrate. The reaction of compound 6 with aromatic aldehydes resulted in the formation of arylidene hydrazides (7). Treatment of 6 with CS2 in the presence of potassium hydroxide (KOH), followed by cyclization with hydrazine hydrate, afforded 4‐amino‐5‐{[3‐(4‐chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol‐4‐yl]methyl}‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thione (9). The condensation of 9 with appropriate aldehydes gave Schiff bases (10), which were converted into Mannich bases (11) in the presence of formaldehyde. All the synthesized compounds were screened for their anti‐lipase and anti‐urease activities. Compounds 7b, 7d, 11b, 11c, and 11d showed moderate‐to‐good lipase inhibitory effects compared to orlistat. Compounds 7b and 7d exhibited better anti‐lipase activity. Furthermore, among the compounds tested, 11a and 11d were found to show high inhibitory effect against urease with IC50 values of 12.39 ± 0.35 and 16.12 ± 1.06 µg/mL, respectively. Compound 11c showed moderate inhibitory activity. The Mannich base containing compound 11 may be a source of good leads for the synthesis of lipase and urease dual inhibitors.

Syntheses and biological activities of new hybrid molecules containing different heterocyclic moieties.

4‐Aryl‐5‐(pyridin‐3‐yl)‐4H‐1,2,4‐triazole‐3‐(thi)oles 5–7, obtained starting from nicotinic acid hydrazide were converted to the corresponding Mannich bases 12–24 by the reaction with several heterocyclic amines in the presence of formaldehyde. The synthesis of S‐alkylated compounds 8–11 was performed from the reaction of the corresponding triazol‐5‐thioles with various alkyl halides. The condensation of carbo(thio)amides 2–4 with 4‐chlorophenacyl bromide afforded the corresponding 1,3‐thia(oxa)zol‐2(3H)‐ylidene]pyridine‐3‐carbohydrazides 25–27. 1,3‐Thia(oxa)zolidine derivatives 28–30 were obtained from the cyclization reaction between compounds 2–4 and ethyl bromoacetate. All newly synthesized compounds were screened for their antimicrobial, antiurease, and antilipase activities. The biological activity studies revealed that all the compounds screened showed good or moderate antimicrobial, antiurease, and/or antilipase activity.

Rapid synthesis and lipase inhibition activity of some new benzimidazole and perimidine derivatives

This study presents a synthesis of new series of some benzimidazole, bisbenzimidazole and perimidine derivatives via microwave technique, which, leads to the good product yields and short reaction times. The structure of newly synthesized compounds was confirmed by 1H NMR and 13C NMR spectra. These compounds were screened for their lipase inhibition activity. Then, all compounds were evaluated with regard to pancreatic lipase activity, and some of the 2-substituted perimidines, bisperimidine and bisbenzimidazole derivatives showed lipase inhibition at various concentrations.

Synthesis and Study of α-Glucosidase Inhibitory, Antimicrobial and Antioxidant Activities of Some Benzimidazole Derivatives Containing Triazole, Thiadiazole, Oxadiazole, and Morpholine Rings

A new series of 2-(4-bromobenzyl)- and 2-(4-fluorobenzyl)-1H-benzimidazole derivatives containing 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, and morpholine rings has been synthesized. The structures of the newly synthesized compounds were confirmed by 1H and 13C NMR and mass spectra, and all substances have been screened for their α-glucosidase inhibitory, antimicrobial and antioxidant activities. Hydrazide, oxadiazole, thiosemicarbazide, and 1,2,4-triazole-3-thiol derivatives showed very good ABTS scavenging activities (IC50 1.94-4.79 μM). Oxadiazole and thiosemicarbazide derivatives also revealed notable DPPH scavenging activity. 5-[(2-(4-Bromobenzyl)-1H-benzimidazol-1-yl)methyl]-1,3,4-oxadiazole-2-thiol was found to be more potent than acarbose. 2-(4-Fluorobenzyl)-1H-benz- imidazole was effective against both Gram-positive and Gram-negative bacteria, especially, M. smegmatis.

Synthesis of Some Heterofunctionalized Penicillanic Acid Derivatives and Investigation of Their Biological Activities

6‐Substituted amino‐penicillanic acid esters were synthesized starting with 6‐apa. The compounds containing a 1,3‐thiazole‐ or 1,3‐thiazolidinone nucleus linked to the penicillanic acid skeleton via a hydrazino linkage were obtained from 6‐apa. The treatment of carbonylamino and carbonothioylamino compounds with 4‐chlorophenacyl bromide or ethyl bromoacetate gave 6‐bis{4‐[1,3‐thiazol(idinone)amino]benzoyl}amino derivatives of 6‐apa. Benzyl derivatives were synthesized in several steps, starting with 4‐aminobenzoyl chloride. The treatment of 4‐{[3‐benzyl‐4‐oxo‐1,3‐thia(oxa)zolidin‐2‐ylidene]amino}benzoyl chlorides with 6‐apa in ethanolic solution produced the 6‐[bis(4‐{[3‐benzyl‐4‐oxo‐1,3‐thiazolidin‐2‐ylidene]amino}benzoyl)amino] derivative of penicillanic acid, while the reaction of the same intermediates in DMF gave the mono‐substituted amino derivative of 6‐apa. The synthesized compounds were screened for their biological activities, and some of them were found to possess good to moderate antimicrobial activity. Moreover, some of the compounds displayed antiurease, anti‐β‐lactamase, and/or antilipase activities.

Design, synthesis and biological activities of some 7-aminocephalosporanic acid derivatives

The treatment of 7-ACA with 4-substituted benzensulfonyl chlorides afforded the compounds containing 4-nitro/aminophenyl sulfonylamino moiety in the cephalosporanic acid skeleton (2, 4). The synthesis of the cephalosporanic acid derivatives containing 1,3-thiazole or 5-oxo-1,3-thiazolidine nucleus and sulfonamide function (8a, 8b, 10) was performed starting from 7-ACA by several steps. The reaction of 7-ACA with [4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]acetyl chloride afforded the corresponding 7-{[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]acetyl}amino derivative (13). The synthesized compounds were screened for their antimicrobial and antiurease activities. Some of them were found to possess good-moderate antimicrobial activity against the test microorganisms. Compound 5d was observed to have moderate anti-urease activity.

Microwave-promoted synthesis and biological activity of some 2-hetarylmethyl-4-(4-hetarylphenyl)-5-methyl-2,4-dihydro-3 H -1,2,4-triazol-3-one derivatives

A series of fused and non-fused 1,2,4-triazole derivatives were prepared starting from ethyl 4-[1-(2-ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]benzoate. Firstly, both ethyl ester groups were simultaneously transformed into hydrazide groups, then into 4-amino-5-mercapto-4H-1,2,4-triazol-3-yl groups using both microwave-assisted and conventional methods. The latter products interacted with 2 equiv of phenacyl bromides, chloroacetone, or chloroacetic acid to form ring assemblies containing two [1,2,4]triazolo-[3,4-b][1,3,4]thiadiazine fragments. Cyclization using 2 equiv of carboxylic acids, urea, or CS2 leads to the corresponding [1,2,4]triazolo-[3,4-b][1,3,4]thiadiazole derivatives. The synthesized compounds were evaluated in regard to their antimicrobial, anti-lipase, and antiurease activities.

Microwave-assisted synthesis of some hybrid molecules containing penicillanic acid or cephalosporanic acid moieties and investigation of their biological activities

Ethyl 4-amino-2-fluorophenylpiperazin-1-carboxylates containing a 1,3-oxazol(idin)e, 5-thioxo-1,2,4-triazole, 1,3,4-thiadiazole, 5-thioxo-1,3,4-oxadiazole, or 1,3-thiazole nucleus were obtained starting from ethyl piperazine-1-carboxylate (1) by several steps. The treatment of amine, 3 or hydrazide, 9 with several aromatic aldehydes generated the corresponding arylmethyleneamino (3a–f) or arylidenehydrazino (12a–c) compounds. The Mannich reaction between the 1,2,4-triazole or 1,3,4-oxadiazole compounds and 7-aca produced cephalosporanic acid derivatives. Penicillanic acid derivatives were obtained when 6-apa was used in the Mannich reactions. The synthesized compounds were screened for their antimicrobial, antilipase, and antiurease activities. Some of them were found to possess good-moderate antimicrobial activity against the test microorganisms. Two compounds exhibited antiurease activity, and four of them displayed antilipase activity.