Cinnoline Scaffold-A Molecular Heart of Medicinal Chemistry?

Abstract

The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties.

Keywords: biological activity; cinnoline; heterocyclic compounds.

Figure 1

Structure of the cinnoline ring system.

Figure 2

Structure of 2-furanmethanol-(5′→11)-1,3-cyclopentadiene-[5,4-c]-1H-cinnoline.

Figure 3

Cinoxacin and its naphthyl ester derivative.

Figure 4

General structure of 6-hydroxycinnoline derivatives.

Figure 5

Cinnolines bearing a sulphonamide moiety with antibacterial and antifungal activity.

Figure 6

General structures of cinnoline based chalcones and cinnoline based pyrazoline derivatives.

Figure 7

General structure of pyrazole based cinnoline-6-sulphonamides.

Figure 8

Selected 4-aminocinnoline-3-carboxamide derivatives with antibacterial and antifungal activity.

Figure 9

General structure of 4-(p-aminopiperazine)cinnoline-3-carboxamide derivatives.

Figure 10

Structure of 4-aminocinnoline-3-carboxamides substituted with five- or six-membered heterocycles.

Figure 11

Cinnoline nucleoside analog acting as a siderophore biosynthesis inhibitor.

Figure 12

N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017).

Figure 13

Example of a cinnoline derivative with polybasic functionalities patented as an efflux pump inhibitor.

Figure 14

Cinnoline derivatives with dual anti-inflammatory and antibacterial activity.

Figure 15

Selected pyrazolo[4,3-c]-cinnoline derivatives.

Figure 16

The most promising phosphodiesterase 4 (PDE4) inhibitor with a cinnoline nucleus.

Figure 17

Urea derivative bearing a cinnoline nucleus evaluated as Vanilloid receptor subtype VR1 (TRPV1) receptor antagonist.

Figure 18

Structure of 4-aminocinnoline-3-carboxamide derivatives that exhibit Bruton’s tyrosine kinase (BTK) inhibition activity.

Figure 19

The most potent cinnoline human neutrophil elastase (HNE) reversible competitive inhibitors.

Figure 20

Cinnoline fused Mannich base derivatives.

Figure 21

Dibenzopyrazolocinnolines with antiparkinsonian activity.

Figure 22

General structures of cinnoline leucine-rich repeat kinase 2 (LRRK2) inhibitors.

Figure 23

Structure of 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines with potent phosphodiesterase 10A (PDE10A) inhibitory activity.

Figure 24

PDE10A inhibitors with improved selectivity.

Figure 25

Selected 3H-pyrazolo[3,4-c]cinnolines that act as potent, selective and brain-penetrant PDE10A inhibitors.

Figure 26

Potent benzocinnolinone analogue of irdabisant with high histamine receptor H₃ H₃R binding affinity.

Figure 27

Cinnoline non-benzodiazepine modulators of γ-aminobutyric acid receptor A (GABA A).

Figure 28

Cinnolinone-diaza analogs of known aminobutyrophenones.

Figure 29

Dibenzo[c,h]cinnoline topoisomerase 1 (TOP1) inhibitors.

Figure 30

The structure of compound ARC-31.

Figure 31

TOP1-acting agents related to ARC-31.

Figure 32

Selected indeno[1,2-c]cinnoline) and benzo[h]indeno[1,2-c]cinnoline derivatives.

Figure 33

General structure of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones.

Figure 34

General structure of 11H-pyrido[3′,2′:4,5]pyrrolo[3,2-c]cinnolines.

Figure 35

Cinnoline based ataxia teleangiectasia mutated (ATM) inhibitors.

Figure 36

Structure of 3-amido-4-anilinocinnoline derivatives exhibiting colony-stimulating factor-1 receptor (CSF-1R) inhibition.

Figure 37

c-Met inhibitor with 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety.

Figure 38

General structure of dihydrobenzo[h]cinnoline-5,6-diones.

Figure 39

Compounds bearing cinnoline moieties evaluated against breast cancer cell lines.

Figure 40

Cinnoline transient receptor potential cation channel, subfamily M, member 5 (TRPM5) inhibitor.