Structure-based design, synthesis, biological evaluation, and molecular docking of novel 10-methoxy dibenzo[b,h][1,6]nap
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02645-x
ORIGINAL RESEARCH
Structure-based design, synthesis, biological evaluation, and molecular docking of novel 10-methoxy dibenzo[b,h][1,6] naphthyridinecarboxamides K. N. Vennila1 B. Selvakumar2 V. Satish2 D. Sunny3 S. Madhuri3 K. P. Elango ●
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Received: 3 July 2020 / Accepted: 29 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 10-methoxy dibenzo[b,h][1,6]naphthyridine carboxylic acid was successfully synthesized from 3-methoxyaniline by a new route. By utilizing a structure-based epharmacophore developed from the active site of 3-phosphoinositide-dependent kinase-1, a series of nine novel 10-methoxy dibenzo[b,h][1,6]naphthyridinecarboxamides was synthesized and characterized by different spectral techniques. Three of them are found to be active by screening against A549 cell line and showed significant anticancer activity when compared to a marketed lung cancer drug, pemetrexed. The molecular docking and in silico pharmacokinetic predictions provide detailed understanding for utilizing the dibenzo[b,h][1,6]naphthyridine scaffold in future drug discovery and development of PDK1 inhibitors. Keywords Dibenzonaphthyridines Phosphoinositide-dependent kinase Epharmacophore Pharmacophore modeling ATP site Molecular docking ●
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Introduction Fused heterocycles always attract chemists due to their broad spectrum of biological applications. Naphthyridine is one such fused bicyclic nitrogen containing a heterocycle reported to show a lot of pharmacological and biological activities. There are many literature examples of [1,8]naphthyridine synthesis, antibacterial, and anticancer activity [1]. Nalidixic acid, a marketed [1,8]naphthyridine analog, is more effective against both Gram-positive and Gram-negative bacteria [2]. Malaridine phosphate is an another well-known antimalarial drug, and vosaroxin is the one that is undergoing phase III clinical
Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02645-x) contains supplementary material, which is available to authorized users. * K. P. Elango [email protected] 1
Department of Chemistry, Gandhigram Rural Institute (Deemed to be University), Gandhigram 624302, India
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Anthem Biosciences Private Limited, Bengaluru 560099, India
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National Institute of Animal Biotechnology, Hyderabad 500049, India
trials for acute myeloid leukemia [3]. Like this, [1,6]naphthyridine has been shown to be a prominent scaffold with drug-like properties [4, 5]. There are several reports on the synthesis and biological activities of naphthyridines, but only a few are on dibenzo[1,6]naphthyridines [6–9]. Hence, several efforts have been made to efficiently synthesize dibenzonaphthyridines. These compounds are also reported as important with significant biological activities in vitro, such as 3-phosphoinositide-dependent kinase-1 inhibition [10, 11], topoisomerase I inhibiti
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