Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents.

Autor: Malathi V; Department of Chemistry, School of Science, Gitam Deemed to be University, Hyderabad, TS, India., Sharon N; Department of Chemistry, School of Science, Gitam Deemed to be University, Hyderabad, TS, India., Padmaja P; Centre for Semio Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India., Lokwani D; Rajarshi Shahu College of Pharmacy, Buldana, Maharashtra, India., Khadse S; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India., Chaudhari P; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India., Shirkhedkar AA; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India., Reddy PN; Department of Chemistry, School of Science, Gitam Deemed to be University, Hyderabad, TS, India. npedaven@gitam.edu., Ugale VG; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India. vinod.ugale@rediffmail.com.; Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agarkar Road, Pune, Maharashtra, 411004, India. vinod.ugale@rediffmail.com.
Jazyk: angličtina
Zdroj: Molecular diversity [Mol Divers] 2023 Aug; Vol. 27 (4), pp. 1809-1827. Date of Electronic Publication: 2022 Oct 10.
DOI: 10.1007/s11030-022-10538-x
Abstrakt: An efficient one-pot three-component reaction for the synthesis of [1,3]dioxolo[4',5':6,7]chromeno[2,3-b]pyridines 4(a-i) has been developed. Synthesis was achieved by reacting sesamol (1), aromatic aldehydes 2(a-i), and 2-aminopropene-1,1,3-tricarbonitrile (3) in the presence of triethylamine at 100 °C under neat reaction condition. Simple operational procedure, broad substrate scope, column chromatography free separations, and high yield of products make it an efficient and largely acceptable synthetic strategy. Synthesized compounds 4(a-i) were further screened for preliminary anticonvulsant activity using MES and scPTZ tests. These analogs were also checked for neurotoxicity and hepatotoxicity. Selected active compounds have been then screened quantitatively to determine ED 50 and TD 50 values. Analog 4h was found effective in both preclinical seizure models with significant therapeutic/toxicity profile (4h: ED 50  = 34.7 mg/kg, MES test; ED 50  = 37.9 mg/kg, scPTZ test; TD 50  = 308.7 mg/kg). Molecular dynamic simulation for 100 ns of compound 4h-complexed with GABA A receptor revealed good thermodynamic behavior and fairly stable interactions (4h, Docking score =  - 10.94). In conclusion, effective synthetic strategy, significant anticonvulsant activity with good toxicity profile and detailed molecular modeling studies led us to anticipate the emergence of these analogs as valid leads for the development of future effective neurotherapeutic agents.
(© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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