Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives

Abstract

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Method: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-compo Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

KOtBu Mediated Alcohol Dehydrogenation Strategy: Synthesis of 2‐Aryl Quinazolinones

“…Quinazolinones are nitrogen‐containing fused heterocycles that show a close resemblance to natural alkaloids, owning to these quinazolinone scaffolds have been employed extensively in synthetic drugs . Functionalized quinazolinone derivatives are largely used in pharmaceutical industries (see Figure 1), [1] particularly as anti‐HIV, [2] antifungal, [3] anti‐inflammatory, [4] anti‐cancer, [5] antimutagenic agents, [6] etc. Several substituted quinazolinone also serve as ligands, as well as DNA binders [7] .…”

Green synthesis of 2‐thioxo‐4‐quinazolinones from 2‐aminobenzamide and isothiocyanates

“…Quinazolinone derivatives have attracted great attention in the field of medicinal chemistry due to their diverse and remarkable pharmacological properties 1 such as anticancer, [2][3][4] anti-inflammatory, 5,6 antibacterial, 7 and antiviral activities, 8 tyrosinase inhibition, 9 and α-glucosidase, and α-amylase inhibitory activities. 10 The 2-thioxo-4-quinazolinones have emerged as potential pharmacophores with many biological activities such as antibacterial activity, [11][12][13] anti-inflammatory activity, 14 selective inhibitors of PSA and Drp1, 15 DHFR inhibitors, [16][17][18][19] antitumor, [20][21][22][23][24] carbonic anhydrase IX and XII inhibitors, 25 allosteric Chk1 kinase inhibitors, 26 tyrosinase inhibitors, 9 and EGFR inhibitors (Figure 1).…”

Synthesis of Coumarin Derivatives: A New Class of Coumarin-Based G Protein-Coupled Receptor Activators and Inhibitors

“…Coumarin derivatives exhibit diverse bioactivities, such as anti-bacterial [ 28 , 29 ], anticoagulant [ 30 ], anti-inflammatory [ 31 , 32 ], anti-tumor [ 33 , 34 , 35 ], and antioxidant effects [ 36 ], etc. [ 37 , 38 , 39 , 40 , 41 , 42 ]. Thus, they have received a large amount of attention from synthetic chemists.…”