Pyrazoline Hybrids as Promising Anticancer Agents: An Up-to-Date Overview

Abstract

Pyrazolines are five-membered heterocycles possessing two adjacent nitrogens. They have attracted significant attention from organic and medicinal chemists due to their potent biological activities and the numerous possibilities for structural diversification. In the last decade, they have been intensively studied as targets for potential anticancer therapeutics, producing a steady yearly rise in the number of published research articles. Many pyrazoline derivatives have shown remarkable cytotoxic activities in the form of heterocyclic or non-heterocyclic based hybrids, such as with coumarins, triazoles, and steroids. The enormous amount of related literature in the last 5 years prompted us to collect all these published data from screening against cancer cell lines, or protein targets like EGFR and structure activity relationship studies. Therefore, in the present review, a comprehensive account of the compounds containing the pyrazoline nucleus will be provided. The chemical groups and the structural modifications responsible for the activity will be highlighted. Moreover, emphasis will be given on recent examples from the literature and on the work of research groups that have played a key role in the development of this field.

Keywords: anticancer; antitumor; conjugates; cytotoxicity; hybrid compounds; nitrogen heterocycles; pyrazolines.

Figure 1

Nitrogen-nitrogen (N-N) heterocyclic anticancer agents that have received approval by FDA in the last decade.

Figure 2

The number of research articles in pyrazolines in the anticancer activities field, excluding reviews and patents throughout the first appearance of a cytotoxic pyrazoline until 2019.

Figure 3

Core structure of pyrazoline ring along with the numbering of the biologically relevant 2-pyrazoline according to common nomenclature.

Figure 4

Chemical structures of anticancer 1-pyrazolines.

Figure 5

Chemical structures of anticancer 3-pyrazolines.

Figure 6

Chemical structures of anticancer clinical drug-pyrazoline hybrids.

Figure 7

Chemical structures of anticancer coumarin-pyrazoline [55,56].

Figure 8

Chemical structures of anticancer coumarin-pyrazoline hybrids [57,58] Amin et al.

Figure 9

Chemical structures of anticancer coumarin-pyrazolines.

Figure 10

Chemical structures of anticancer quinoline and quinolinone-pyrazolines.

Figure 11

Chemical structures of anticancer pyrazoline hybrids with various benzene-fused heterocycles.

Figure 12

Chemical structures of anticancer indole pyrazoline conjugates [81].

Figure 13

Chemical structures of anticancer oxindole and tetrahydro-methanoisondolodione-pyrazoline hybrids.

Figure 14

Chemical structures of anticancer isatin-pyrazoline hybrids.

Figure 15

Chemical structures of anticancer oxygen and sulfur analogues of indole-pyrazoline hybrids.

Figure 16

Chemical structures of anticancer thiazolyl-pyrazolines.

Figure 17

Chemical structures of anticancer thiazolyl-pyrazolines.

Figure 18

Chemical structures of benzothiazolyl-pyrazolines tested for their anticancer activity.

Figure 19

Chemical structures of anticancer thiazolidinone-pyrazolines.

Figure 20

Chemical structures of anticancer thiazolidinone pyrazoline conjugates.

Figure 21

Chemical structures of anticancer pyrazole-pyrazoline hybrids.

Figure 22

Chemical structures of anticancer imidazole containing pyrazoline hybrids.

Figure 23

Chemical structures of anticancer pyrimidine and oxazoline containing pyrazoline hybrids.

Figure 24

Chemical structures of anticancer triazole containing pyrazoline hybrids.

Figure 25

Chemical structures of anticancer triazole containing pyrazoline hybrids.

Figure 26

Chemical structures of anticancer a tetrazole and an oxodiazole containing pyrazoline hybrids.

Figure 27

Chemical structures of anticancer D-ring substituted or fused steroidal pyrazoline hybrids.

Figure 28

Chemical structures of anticancer B-ring fused steroidal and ursolate pyrazoline hybrids.

Figure 29

Chemical structures of other non-classified pyrazoline hybrids.