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Paper | Regular issue | Vol 104, No. 2, 2022, pp.288-309
Published online, 19th November, 2021
DOI: 10.3987/COM-21-14573
■ Design and Synthesis of New Quinoline Linked to Pyranotriazolopyrimidines Conjugates as Novel Targets to Discover Promising Anti-SARS-COV-2

Faisal K. Algethami,* Salma Jlizi, Mansour Znati, Naoufel Ben Hamadi, Anis Romdhane, Mohamed R. Elamin, Lotfi Khezami, and Hichem Ben Jannet*

*Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Team: Medicinal Chemistry and Natural Products, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, 5019 Monastir, Tunisia

Abstract

Simple one-pot synthesis of 2-aminopyranoquinoline-3-carbonitriles 2a-d at room temperature from available 8-hydroxyquinaldine, malononitrile, and substituted aromatic aldehydes was realized. Compounds 2a-d were converted into iminoethers 3a-d, condensed with a series of hydrazide under microwave irradiation to yield novel pyranotriazolopyrimidines fused to quinoline 4a-f. Compound 4c, with a cyanomethyl group, was treated with some salicylic arylaldehydes to give the corresponding new pyranotriazolopyrimidine-chromen 5a-c in good yields. Finally a new series of arylidenes linked to triazolopyrimidopyrano[3,2-h]quinoline 6a-h were designed and synthesized by the reaction of 4a,c, both bearing a cyanomethyl group, with a series of arylaldehydes. The structures of all the compounds were evidenced by 1H/13C NMR, IR, and ESI-HRMS. The present study focuses also to predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to find in advance whether this protein can be targeted by the compounds 4c, 4f, 5a-c and 6a-h thus synthesized. The docking scores of these compounds were compared to that of the co-crystallized native ligand inhibitor (N3) used as a reference standard. The results showed that all the synthesized compounds (4c, 4f, 5a-c and 6a-h) gave interesting binding scores compared to the N3 inhibitor. It has been found that compounds 4c, 4f, 5a and 5b achieved considerably similar binding scores and modes of interaction than the co-crystallized inhibitor N3 indicating good affinity towards SARS-CoV-2 Mpro. Conversely, the derivatives 6h and 5c showed binding energy scores (-8.9 and -8.8 kcal/mol, respectively) higher than the Mpro N3 inhibitor (-7.0 kcal/mol), revealing, in their turn, strong interaction with the target protease. However, their interactions were not entirely comparable to those of reference N3.