Chalcone Derivatives: Promising Starting Points for Drug Design

Abstract

Medicinal chemists continue to be fascinated by chalcone derivatives because of their simple chemistry, ease of hydrogen atom manipulation, straightforward synthesis, and a variety of promising biological activities. However, chalcones have still not garnered deserved attention, especially considering their high potential as chemical sources for designing and developing new effective drugs. In this review, we summarize current methodological developments towards the design and synthesis of new chalcone derivatives and state-of-the-art medicinal chemistry strategies (bioisosterism, molecular hybridization, and pro-drug design). We also highlight the applicability of computer-assisted drug design approaches to chalcones and address how this may contribute to optimizing research outputs and lead to more successful and cost-effective drug discovery endeavors. Lastly, we present successful examples of the use of chalcones and suggest possible solutions to existing limitations.

Keywords: chalcone derivatives; chalcone synthesis; computer-assisted drug design; molecular modification strategies; natural products.

Figure 1

Structural and numerical representations of chalcone scaffold.

Figure 2

Chemical structures of approved and clinically tested chalcones.

Scheme 1

The Claisen-Schmidt condensation.

Scheme 2

Carbonylative Heck coupling reaction.

Scheme 3

Coupling reaction.

Scheme 4

Sonogashira isomerization coupling. EWG: electron withdrawing group.

Scheme 5

Continuous-flow deuteraction reaction.

Scheme 6

Suzuki–Miyaura coupling reaction.

Scheme 7

One-pot synthesis of chalcones.

Scheme 8

Solid acid catalyst mediated synthesis.

Figure 3

Bioisosterism represented by replacing the hydrogen (red) with a fluorine (blue) [45].

Figure 4

Bioisosterism represented by the replacing the hydroxyl and chloride groups (red) with a carboxylic acid and hydrophobic groups (blue) [46].

Figure 5

Bioisosterism represented by the replacing the double bond of the enone (blue) with a thiophene (red) [47].

Figure 6

Molecular hybrid obtained from the combination of chalcones (red) and N-aryl piperazine moiety (blue) [50].

Figure 7

Molecular hybrid obtained from a combination of 4'-chlorochalcone (red) and chloroquine (blue) [57].

Figure 8

Molecular hybrids obtained from combination of well-known vasodilators (nitrendipine or furoxan, highlighted by purple and blue colors, respectively) and chalcones [61].

Figure 9

Molecular hybrids obtained from a combination of Fluvastatin (purple), fenofibrate (blue), and chalcones (red) [67].

Figure 10

Latentiation represented by the replacing the hydroxyl (red) with a phosphate (blue) [77].

Figure 11

Latentiation represented by the replacing the amine (red) with an l-Lysine-l-Proline (blue) [78].

Figure 12

Antitubercular 5-nitro-substituted heteroaryl chalcones prioritized by our QSAR-driven drug design strategy [139].

Figure 13

Chalcones with anticancer activity identified by integration of ligand-based pharmacophore screening and molecular docking studies [142].

Figure 14

Time-dependent histone deacetylase 2 selective inhibitors identified by integration of quantum mechanics and quantum mechanics/molecular mechanics strategies [147].

Figure 15

Anti-leishmanial chalcone-dihydropyrimidine hybrids (red and blue, respectively) prioritized by molecular docking studies [151].

Figure 16

Anti-leishmanial 5-nitro-substituted heteroaryl chalcones identified by integration of pharmacophore screening and molecular docking studies [154].