Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

Abstract

Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization's list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2-2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold's potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure-activity relationship studies that should be considerably useful for the future of the field.

Keywords: N-heterocycles; amastigotes; leishmania; promastigotes; quinolines.

Figure 1

Currently used antileishmanial agents.

Figure 2

Quinoline scaffold (9) and respective numbering system.

Figure 3

Some examples of quinoline-based approved drugs.

Figure 4

Structural–antileishmanial activity relationship study of quinoline derivatives (16) reported until mid-2013 [20].

Figure 5

Structure-antileishmanial activity relationship of quinolinium salts (17), with an emphasis on derivative 18.

Figure 6

(A) Most promising 2-arylquinoline derivative (19) against L. amazonensis; (B) Structure-antileishmanial activity relationship study of Cinchona alkaloid-bile acid hybrids (20) against L. mexicana promastigotes.

Figure 7

(A) Structure-antileishmanial activity relationship study of 2-substituted quinolines (21). (B) Structures of derivatives 22 and 23, the two most promising antileishmanial agents. (C) Structure of derivative 24, an antileishmanial agent developed through an optimization process.

Figure 8

Structure-antileishmanial activity relationship study of triazino indole-quinoline hybrids (25), with particular emphasis on derivative 26.

Figure 9

(A) Structure-antileishmanial activity relationship study (29) with a particular emphasis on derivatives 30 and 31 for being the most active analogs against L. major promastigotes and amastigotes, respectively. (B) Structure-antileishmanial activity relationship study (32) of the optimization process, with particular emphasis on derivative 33.

Figure 10

Ferrocenylquinoline derivatives (34–36), organometallic hybrids with promising antileishmanial properties against L. donovani and L. major.

Figure 11

Structure of two promising antileishmanial compounds (37 and 38) against both L. panamensis and L. major.

Figure 12

Quinoline-containing selenocyanates (39 and 40) and diselenides (41) with antileishmanial activity.

Figure 13

Promising 4-substituted quinolines (42 and 43) against L. amazonensis and L. braziliensis

Figure 14

Structure-antileishmanial activity relationship study of quinolinyl-oxadiazole thiosemicarbazide hybrids (44), with emphasis on the most active derivative (45).

Figure 15

Quinoline-based GDP-MP competitive inhibitors (46–48) against L. donovani and L. mexicana.

Figure 16

Structures of the most promising chalcone-quinoline (49) and furanchalcone–quinoline (50) hybrids against L. panamensis.

Figure 17

Clioquinol (51), a promising antileishmanial agent.

Figure 18

Structure-antileishmanial activity relationship study of quinoline-triazole hybrids (54), with particular emphasis to the most promising derivatives (52 and 53).

Figure 19

Most promising quinoline derivatives (55–57) against L. (L.) amazonensis amastigotes.

Figure 20

Most promising quinolinic salt (58) developed against L. amazonensis and L. braziliensis.

Figure 21

Structure of the most promising quinolinyl-phosphine oxide (59) against L. infantum.

Figure 22

Structure-antileishmanial activity relationship study of quinoline-thiadiazole hybrids (60) against L. major intracellular amastigotes.

Figure 23

Structure-antileishmanial activity relationship study of aryl derivatives of 2- and 3-aminoquinoline (61) against L. mexicana promastigotes.

Figure 24

Structure-antileishmanial activity relationship study of quinoline-4-carboxylic acids (62) against L. donovani promastigotes, with emphasis on the most active compound (63).

Figure 25

Structures of the most promising 4-aminostyrylquinolines (65 and 66) as antileishmanial agents against both L. donovani and L. pifanoi.

Figure 26

Structure -antileishmanial activity relationship study of quinoline-metronidazole hybrids (69), with emphasis on the most active derivatives (67 and 68).

Figure 27

Structure-antileishmanial activity relationship study of thiazole orange analogs (70), with particular emphasis on the most active derivative (71).

Figure 28

Structure-antileishmanial activity relationship studies of quinoline derivatives against L. major (74) and L. donovani (75), with particular emphasis on the most active quinoline against each species (72 for L. major and 73 for L. donovani).

Figure 29

Promising quinoline derivatives against L. (V) panamensis (76 and 77) and L. amazonensis (78 and 79).

Figure 30

Structure-antileishmanial activity relationship study of 3-arylquinolines (83), with focus on the most active derivatives (80–82).

Figure 31

Structure-antileishmanial activity relationship study of quinoline-1,2,3-triazole hybrids (85), with emphasis on the most active derivatives from the series (84).

Figure 32

Structure-antileishmanial activity relationship study of quinoline-isatin hybrids (86) against L. major.

Figure 33

Structure of a quinoline dimer with promising antileishmanial properties against L. infantum promastigotes.

Figure 34

Structure-antileishmanial activity relationship study of quinoline-piperazine/pyrrolidine hybrids against L. donovani (90), with emphasis on the most promising derivatives (88 and 89).