Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]Pyrido[1,2-a]Pyrimidine-Based Cytotoxic Agents

Mabrouk Horchani
,
Niels V. Heise
ORCID logo ,
Sophie Hoenke
ORCID logo ,
Rene Csuk
* ORCID logo ,
Abdel Halim Harrath
ORCID logo ,
Hichem Ben Jannet
* ORCID logo ,
Anis Romdhane
Version 1 : Received: 7 September 2021 / Approved: 10 September 2021 / Online: 10 September 2021 (15:07:59 CEST)

A peer-reviewed article of this Preprint also exists.

Horchani, M.; Heise, N.V.; Hoenke, S.; Csuk, R.; Harrath, A.H.; Jannet, H.B.; Romdhane, A. Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents. Int. J. Mol. Sci. 2021, 22, 10258. Horchani, M.; Heise, N.V.; Hoenke, S.; Csuk, R.; Harrath, A.H.; Jannet, H.B.; Romdhane, A. Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents. Int. J. Mol. Sci. 2021, 22, 10258.

Abstract

To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivatives 7a-l have been designed and synthesized via cyclocondensation reactions of pyrazolo-enaminone 5 with a series of arylidene malononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole (3). The structures of the target compounds 7a-l were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the conjugate 7e was the most active towards many cell lines with EC50 values ranging between 9.1 and 13.5 µM, respectively. Moreover, in silico docking studies of 7e with six anticancer drug targets, i.e. DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX also was performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

Keywords

pyrazolo-pyrido-pyrimidines; cytotoxicity; tumor cell lines; SAR; in silico docking.

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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