Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

Abstract

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.

Keywords: anti-Alzheimer; antimicrobial; antitumor; molecular hybridization; pharmacophore; phenothiazine.

Figure 1

Three successfully marketed hybrid molecules.

Figure 2

Examples of drug molecules containing phenothiazines scaffold: Methylene Blue, Chlorpromazine; Thioridazine, Fluphenazine, Promethazine, and Prophenamine [8].

Figure 3

Chemical structure of 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-10-ethyl-7-phenyl-10H-phenothiazine (1), an antitumor hybrid.

Figure 4

Chemical structures of the most active phenothiazine-1,2,3 triazole hybrids with antiproliferative activity.

Figure 5

Chemical structures of 1,2,3-triazole and diazaphenothiazine hybrids with antiproliferative effects.

Figure 6

Chemical structures of N-(2-hydroxybutyl)-2-aminophenothiazines bound to 4-methoxyphenyltetrazole with P-glycoprotein inhibitory activity.

Figure 7

Chemical structures of hybrids bearing the phenothiazine core and N-acylated 1,2,3-triazole with antitumor interest.

Figure 8

Chemical structures of phenothiazine-indolizine derivatives with antiproliferative activity.

Figure 9

Chemical structures of the most active pyrazolo-phenothiazine and similar compounds with FTase inhibitor activity.

Figure 10

Chemical structures of amino acid-phenothiazine with FTase inhibitory activity. The most promising FTase inhibitor was 16d.

Figure 11

Chemical structures of chalcone-phenothiazine hybrids with antitumor interest.

Figure 12

Chemical structure of the most potent antiproliferative compound synthesized by Brem et al. (2017): 2-(naphthalen-1-yl)-10-methyl-10H-thiazolo[5,4-b]-phenothiazine [38].

Figure 13

Chemical structure of the most active phenothiazinyl-thiazolyl-hydrazine derivatives with cytotoxic effects.

Figure 14

Chemical structure of phenothiazine-based hybrids linked with analogs of phenstatin [42,46].

Figure 15

Chemical structure of phenothiazine-dithiocarbamate (23) hybrid with potent anticancer activity.

Figure 16

Chemical structure of the most potent phenothiazinyldihydropyridine dicarboxamides hybrids as antiproliferative agents.

Figure 17

Chemical structure of the most potent phenothiazinyldihydropyridine hybrids as antitumor compounds.

Figure 18

Chemical structure of the most potent hybrids with sulfonamide moiety with anticancer activity.

Figure 19

The chemical structure of phenothiazine-sphingolipid hybrid 33.

Figure 20

Chemical structure of the three most potent tacrine-phenothiazine hybrids with interest in Alzheimer’s disease.

Figure 21

General chemical structure of N-acylaminophenothiazine hybrids with interest in neurodegenerative diseases.

Figure 22

Chemical structures of N-carbonyl compounds butyrylcholinesterase inhibitors with no neurotransmitter receptor interactions.

Figure 23

Chemical structure of hybrid 42 designed by Kubota et al. (2009) with antihistaminic activity [63].

Figure 24

Chemical structure of phenothiazine hybrids with EPIs INF55 (43 and 44) and INF271 (45).

Figure 25

Chemical structure of isoxazole–phenothiazine hybrids with antibacterial effects.

Figure 26

Chemical structure of the most potent phenothiazine-1,3,4-thiadiazoles developed by Ramprasad et al. (2015) [73].

Figure 27

Chemical structure of phenothiazine triazole-based antitubercular agents.

Figure 28

Chemical structure of verapamil phenothiazine hybrids with antitubercular interest.

Figure 29

Chemical structure of a phenothiazines alkyltriphenylphosphonium hybrid (54) with activity against M. tuberculosis.

Figure 30

Chemical structures of phenothiazine linked with-chalcones, pyrazolines and isoxazolines demonstrating antitubercular activity.

Figure 31

Chemical structures of phenothiazine-triazole hybrids with potent antitubercular activity.

Figure 32

Chemical structure of compound 61, an antimalarial that acts synergistically with chloroquine.

Figure 33

Chemical structure of compound 62 with antifungal activity.

Figure 34

Chemical structure of the most active phenothiazine-CB1-antagonist hybrids.

Figure 35

Chemical structures of compounds with antiplatelet and analgesic effects synthesized by Silva et al. (2004) [89].