Biginelli Reaction Mediated Synthesis of Antimicrobial Pyrimidine Derivatives and Their Therapeutic Properties

Abstract

Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure-activity relationship in the studied compounds.

Keywords: Biginelli reaction; antimicrobials; antioxidant; antitubercular; catalyst; dihydropyrimidininones.

Scheme 1

The Biginelli dihydropyrimidone synthesis.

Figure 1

Schematic representation of the synthesis and therapeutical properties of antimicrobial Biginelli mediated Pyrimidine compounds.

Scheme 2

Synthesis of quinazolines 2a–2h using Biginelli reaction.

Scheme 3

Synthesis of 2-amino-5-cyano-6-hydroxy-4-arylpyrimidines 3a–3l.

Scheme 4

Synthesis of compounds 4a–4h and 6a–6h.

Scheme 5

Synthesis of compounds 7a–7h.

Scheme 6

Synthesis of compounds 8a–8d and 9a–9d.

Scheme 7

Synthesis of compounds 14a–14l.

Figure 2

Chemical structures of the comounds 15a–15e and 16a–16e.

Scheme 8

Synthesis of compounds 17–26 and 17–26(a–d).

Scheme 9

Synthesis of compounds 28a–28b.

Scheme 10

Synthesis of compounds 31a–31n.

Scheme 11

Synthesis of compounds 35a–35p.

Scheme 12

Synthesis of compounds 36, 37, and 38.

Figure 3

Chemical structures of compounds 39a–39b, 40a–40c, 41 and 42.

Scheme 13

Synthesis of compounds 43a–43d, 44a–44d, and 45a–5d.

Scheme 14

Synthesis of compounds 46a–46h.

Scheme 15

Synthesis of compounds 47a–47f and 48a–48f.

Scheme 16

Synthesis of compounds 49a–49f.

Scheme 17

Synthesis of compounds 50a–50e.

Scheme 18

Synthesis of compounds 51–61.

Figure 4

Chemical structures of compounds 62a–62d and 63.

Figure 5

Chemical structures of compounds 64–66.

Scheme 19

Synthesis of compounds 67a–67e and 68a–68e.

Figure 6

Extra precision Glide docking of human rRNA (3J3D) with (a) amikacin and (b) compound 68e.

Scheme 20

Synthesis of compounds 71a–71c and 72a–72c.

Figure 7

Chemical structures of compounds 73a–73c, 74a–74b, and 75a–75b.

Scheme 21

Synthesis of compounds 76a–76e and 77a–77e.

Figure 8

Chemical structures of compounds 78a–78f and 79.

Scheme 22

Synthesis of compounds 80a–80e and 81a–81e.

Figure 9

Chemical structures of compounds 82a–82e and 83–85.

Figure 10

Chemical structures of compounds 86, 87, 88, and 89.

Scheme 23

Synthesis of compounds 90a–90c and 92a–92c.

Figure 11

Chemical structures of compounds 93 and 94.

Scheme 24

Synthesis of compounds 97a–97j.

Scheme 25

Synthesis of compounds 98a–98g.

Scheme 26

Synthesis of compounds 99a–99e and 100a–100e.

Figure 12

Chemical structures of compounds 101.

Scheme 27

Synthesis of the compounds 102a–102i catalyzed by MnFeCaFe₂O₄@starch@aspartic acid MNPs.

Figure 13

Structure−activity relationship of compounds 103a–103f.

Scheme 28

Synthesis of compounds 104a–104c.

Scheme 29

Synthesis of compounds 105a–105d.

Scheme 30

Synthesis of compounds 106 and 107.

Scheme 31

Synthesis of compounds 108a–108g.

Figure 14

3D and 2D interaction plots of docked compound 108e within the binding cavity of 1KZN.

Scheme 32

Synthesis of compounds 109, 110a–110c, 111a, 111b, 112, 113a, and 113b.

Figure 15

Chemical structure of compounds 14d, 114, 115a, and 115b.

Scheme 33

Synthesis of compounds 116a–116h.

Figure 16

Chemical structure of compounds 117a–117b, 118a–118b.

Scheme 34

Synthesis of compounds 119a–119d.

Figure 17

Chemical structure of compounds 37a–37d.

Figure 18

Chemical structures of compounds 77f–77h.

Figure 19

Chemical structures of compounds 92a, 92b, 92e–92h.

Figure 20

Chemical structures of compounds 62e, 62f, and 62g.

Figure 21

Intermolecular interactions with of the compounds 47a (A) and 48a (B) (Scheme 13) at the active site of human inosine monophosphate dehydrogenase (IMPDH) type II (PDB ID: 1NFB), where Cys331 is the catalytic residue. Both compounds exhibited imperative hydrogen bonding with a number of explicit residues of the active site of IMPDH.

Figure 22

Chemical structures of compounds 105e, 105f, 105h and 105i.

Figure 23

Chemical structures of compounds 120, 121, and 122.