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Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease.

ABSTRACT: The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the in vitro fluorometric method. Additionally, amyloid beta (Aβ)-aggregation inhibitory effects of active compounds were evaluated by means of an in vitro kit-based method. The biological evaluation showed that compounds 4a, 4d, 4f, 4h, 4k and 4m displayed significant activity against AChE and MAO-B enzymes. Compound 4f displayed inhibitory activity against AChE and MAO-B enzyme with IC₅₀ values of 23.4 ± 1.1 nM and 40.3 ± 1.7 nM, respectively. It has been revealed that compound 4f may have the potential to inhibit AChE and MAO-B enzymes, as well as the ability to prevent the formation of beta amyloid plaques accumulated in the brains of patients suffering from AD. In silico studies also support the obtained biological activity findings. Compound 4f provided strong interactions with the active site of both enzymes. In particular, the interaction of compound 4f with flavin adenine dinucleotide (FAD) in the MAO-B enzyme active site is a promising and exciting finding.

SUBMITTER: Karaca S

PROVIDER: S-EPMC9389372 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease.

Karaca Şevval Ş Osmaniye Derya D Sağlık Begum Nurpelin BN Levent Serkan S Ilgın Sinem S Özkay Yusuf Y Karaburun Ahmet Çağrı AÇ Kaplancıklı Zafer Asım ZA Gundogdu-Karaburun Nalan N

RSC advances 20220819 36

The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the <i>in vitro</i> fluorometric method. Additionally, amyloid beta (Aβ)-aggregation inhibitory effects of active compounds were eva ...[more]

PMID: 36090440

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Project description:The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole N-arylsulphonylhydrazone with N-aryl-2-cyano-3-(dimethylamino)acrylamide, N-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of N-arylsulfonylpyridones 6a-d (yield 60-70%) and 12a-c (yield 50-60%),N-(2-(benzo[d]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide 14a-c (yield 60-65%), 4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a-c (yield 65-75%), and N'-(2-(benzo[d]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide 19a-e (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against S. aureus with an MIC range of 0.025 to 2.609 mM. The most active compound, 16c, exhibited superior activity against the S. aureus strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, 16a-c, had IC50 values comparable to the standard drug and revealed that compound 16b was the most active compound with an IC50 value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC50 value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds 16a-c are linked by two arene-H interactions with Lys220 within the PABA pocket.

Dataset Information

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease.

Publications

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease.

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