Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives

Abstract

Pyrazole and its derivatives are considered a privileged N-heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.

Keywords: biological activity; drug discovery; medicinal chemistry; multicomponent reactions (MCRs); pyrazole derivatives.

Figure 1

Bibliometric graphic depicting the percentage of articles associated with each biological activity screened from 2015 to date [data were collected searching in Scopus for the keywords: “pyrazole derivatives”, “biological activity”, and “multicomponent reactions”].

Scheme 1

Taurine-catalyzed four-component synthesis and in silico-based analysis of 1,4-dihydropyrano[2,3-c]pyrazoles 6 and 7.

Figure 2

Molecular docking of compound 7 (R = 4-NO₂C₆H₄) with Staphylococcus aureus wild-type DHFR (PDB ID: 2w9g). The left panel shows the zoomed-in view of the ligand interactions with the DHFR active site amino acid residues in the 3D space. The right panel shows the 2D representation of the array of ligand−protein interactions. Hydrogen bond formation is indicated by the green dotted line, whereas hydrophobic interactions are indicated by the spiked arcs. Image adapted from Mali et al. [26].

Scheme 2

Three-component synthesis of pyrazoles 16a–c with antimicrobial activity.

Figure 3

Docking molecular of the compound 21a (magenta) with crucial residues of thymidylate kinase target protein (PDB ID: 4QGG) from Staphylococcus aureus. Image adapted from Barakat et al. [31].

Scheme 3

Four-component synthesis of pyrazole-based pyrimido[4,5-d]pyrimidines 33 mediated by [Bmim]FeCl₄.

Scheme 4

Proposed mechanism for the synthesis of pyrazole-based pyrimido[4,5-d]pyrimidines 33 mediated by [Bmim]FeCl₄ (IL).

Figure 4

Docking molecular of indenopyrazole 37d with crucial residues of DNA gyrase of Escherichia coli (PDB ID: 1KZN). Image adapted from Mor et al. [36].

Figure 5

Visual representation of ciprofloxacin docked with 5BTC, showing hydrophobic–hydrophobic interaction and hydrogen bonding with ARG 128:A, as shown by Vida. Image adapted from Elshaier et al. [65].

Figure 6

Visual representation of compounds 61c, 61o, and 61l docked with 5BTC, showing no hydrogen bond interaction, as shown by Vida. Image adapted from Elshaier et al. [65].

Figure 7

Visual representation of compound 61d docked with 4URM and overlay with 61c, 61a, and 61f. The compounds showed hydrogen bonding between the sulfur of the pyrimidine ring and ASN 145:A, as shown by Vida. Image adapted from Elshaier et al. [65].

Scheme 5

Three-component synthesis of pyrazolo-oxothiazolidine derivatives 99 as antiproliferative agents.

Scheme 6

Three-component synthesis of (E)-2-(2-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinyl)-4-arylthiazoles 100 as apoptosis inducers.

Scheme 7

Three-component synthesis and anticancer activity of imidazo[1,2-b]pyrazole-7-carboxamide derivatives 101.

Scheme 8

Four-component synthesis of 4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2-hydroxy-6-(naphthalen-1-yl)nicotinonitrile 107 with anticancer activity.

Scheme 9

Three-component synthesis of pyrazolo[3,4-d]pyrimidin-4-ol derivatives 109 with anticancer activity.

Scheme 10

Three-component synthesis of copper(I) complexes 111 with pyrazole-linked triphenylphosphine moieties as mitochondria- and nucleolus-labelling probes.

Scheme 11

Four-component synthesis and anticancer evaluation of 1,2,3-triazolyl-pyridine hybrids 113.

Scheme 12

Three-component synthesis and anticancer evaluation of 3H-pyrazolo[4,3-f]quinoline derivatives 116 and 117. Reaction conditions: (a) (i) EtOH, reflux, 2 h, and (ii) cyclic ketone 44, catalyst HCl, reflux, 12 h; (b) (i) THF, reflux, 2 h, and (ii) acyclic ketone or acetophenone 44 and I₂ (10 mol%), reflux, 12 h.

Scheme 13

One-pot four-component synthesis and anticancer evaluation of 3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives 121.

Scheme 14

Microwave-assisted four-component synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles 124 as anticancer agents.

Scheme 15

Three-component synthesis and anticancer evaluation of thiazolyl-based pyrazoles 126.

Scheme 16

Three-component synthesis and anticancer activity of new 4-(4-oxo-4H-chromen-3-yl)pyrano[2,3-c]pyrazoles 128a−d and 5-(4-oxo-4H-chromen-3-yl)pyrano[2,3-d]pyrimidines 129a−d.

Scheme 17

Three-component synthesis and antifungal activity of highly functionalized 1,2,4-triazole-5(4H)-thiones 132 and 134.

Figure 8

Ligand–receptor interaction profiles by molecular docking. (A) Interactions between 4WMZ and 61h, and (B) interactions between 4WMZ and 61l. Image adapted from Elshaier et al. [65].

Figure 9

Docking molecular of the compound 21o with N-myristoyl transferase (PDB ID code: 1IYL) from Candida albicans. Image adapted from Barakat et al. [31].

Scheme 18

(a) Three-component synthesis of fused indolo-pyrazoles 136 for evaluation of their antifungal activity, (b) plausible mechanism for the synthesis of compounds 136.

Scheme 19

One-pot four-component synthesis and antifungal activity of benzylpyrazolyl-coumarin derivatives 139.

Scheme 20

Na₂CaP₂O₇-Catalyzed four-component synthesis of pyrano[2,3-c]pyrazole derivatives 140 and evaluation of their antioxidant activity.

Scheme 21

Three-component synthesis of the pyrano[2,3-c]pyrazole-5-carbonitrile 141 and evaluation of its antioxidant activity.

Scheme 22

Three-component synthesis of tetrahydrobenzo[b]pyran derivatives 142 with antioxidant activity.

Scheme 23

Pseudo four-component synthesis of imidazolylpyrazoles 144 as α-glucosidase inhibitors.

Figure 10

(A) Overall structure of the oligo-1,6-glucosidase (PDB ID: 3A4A) from Saccharomyces cerevisiae with compound 144j, and (B) 2D interactions for compound 144j. Image adapted from Chaudhry et al. [137].

Figure 11

(A) The overall structure of the oligo-1,6-glucosidase (PDB ID: 3A4A) from Saccharomyces cerevisiae with compound 145f, and (B) 2D interactions for compound 145f. Image adapted from Chaudhry et al. [138].

Scheme 24

Three-component synthesis of pyrazole-triazolopyrimidine hybrids 147 as α-glucosidase inhibitors.

Scheme 25

The plausible mechanism for the synthesis of pyrazole-triazolopyrimidine hybrids 147.

Figure 12

3D Interactions of compounds 151g, 151h, and acarbose with binding sites of Aspergillus oryzae α-amylase (PDB ID: 7TAA). Image adapted from Duhan et al. [140].

Figure 13

3D Interactions of indenopyrazoles 37j (left) and 37k (right) with binding sites of Aspergillus oryzae α-amylase (PDB ID: 7TAA). Image adapted from Mor et al. [36].

Figure 14

(a) 2D model enumerating the interactions between ligand 153c and InhA enzyme, (b) 3D model of compound 153c in the binding pocket of the InhA enzyme. Image adapted from Bhatt et al. [147].

Scheme 26

Plausible mechanism for the ultrasound-assisted multicomponent synthesis of spirooxindolopyrrolizidine derivatives 157.

Scheme 27

Three-component synthesis of densely substituted pyrazolo [3,4-b]pyridines 158 as antimalarial agents.

Scheme 28

Pseudo-four-component synthesis of imidazolylpyrazoles 165 as antiurease agents.

Figure 15

3D and 2D Interactions of compounds 165k and 165l with the amino acids of 4GY7. Image adapted from Chaudhry et al. [164].

Scheme 29

Microwave-assisted three-component synthesis of pyrazolo-tetrahydroquinolinones 166 as GSK3α and GSK3β inhibitors.