Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options

Abstract

Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area.

Keywords: Chagas disease; Malaria; covalent target enzyme inhibitors; sleeping sickness.

Scheme 1

Simplified scheme showing the formation of a covalent complex and its constants. P-I is the complex in which P and I form non-covalent interactions between them. P-I* consists of covalent binding between the two molecules.

Figure 1

Trypanosoma brucei oxidizing cycle. Adapted from [38,39,99].

Scheme 2

TS₂ reduction reaction.

Figure 2

(a) Main compounds studied for HAT treatment by covalent inhibition and parameters observed; (b) Protein interaction with the molecule 6. Adapted from [35].

Figure 3

The nomenclature regarding papain-like proteins according to Schechter and Berger [7].

Figure 4

Sequence of studies and hit compounds from [24,27,29,31,32].

Figure 5

(a) Docking experiments with 19 and RD. In this figure, hydrogen bonds between several residues and 11 can be observed, and possibly facilitate the nucleophilic action of Cys₂₅. Adapted from [9]; (b) Docking experiments carried out by Ettari et al. with 11 and RD [8]; (c) Docking experiments carried out by Previti et al. with 15 and RD [10]; (d) 14 and RD, active site [11].

Figure 6

(a) Leads synthesized in [17,18] (b) Docking experiment with compound 22 and RD (adapted from https://www.zotero.org/google-docs/?xzROTL (accessed on 18 March 2023) [17,18]).

Figure 7

Compounds with benzodiazepine scaffold linked to bromoisoxaline as a warhead, as employed by Ettari et al. [21], and maintaining the adamantyl group [37,38].

Figure 8

Compound 21 optimization towards RD interaction [38,39,40].

Figure 9

(a) Mechanism of action of 21 towards RD and its irreversible inhibition, adapted from [23,24]. (b) Mechanism of action of 33 towards RD and its irreversible inhibition adapted from [24].

Figure 10

Compound 34 and its possible interaction towards RD. Adapted from [24].

Figure 11

Non-peptidic compounds synthesized by McShan et al. [25].

Figure 12

Mechanism of action concerning the covalent fragments studied by McShan et al. [25].

Figure 13

Molecules derived from previously mentioned and attempts of lead optimization [22,26,27].

Figure 14

Adapted from [22] Compound 41 and its interactions with RD obtained from docking experiments. There is no interaction of thioimidate with the target according to the docking experiment.

Figure 15

Structure and biological parameters of hit compounds [28,29].

Figure 16

Compound 45 and its interactions towards RD [29], highlighting the intramolecular hydrogen bond.

Figure 17

(a) Hit compounds with interesting activity towards pteridine reductase; (b) Hit compounds with interesting activity towards CLK1, adapted from [43]; (c) ligand interaction site taken from Crystal structure of CLK1 and 49. Adapted from [48]; (d) Compound 50—covalent inhibitor of CatL; (e) Hits compounds from [30].

Figure 18

(a) Compound 54 and (b) 55 by [45,46], respectively. (c) Hit compounds obtained [31,47].

Figure 19

Distribution of pockets that will be used in this part of review. Also, it is noted that the parts of molecule which are nearest to these pockets are P1, P2, and P3. pdb: 4QH6.

Figure 20

Hit compounds in diverse studies [50,52,53,54].

Figure 21

Proposed mechanism of covalent inhibition concerning nitrile compounds such as the ones shown in Figure 19 [55].

Figure 22

Covalent docking experiments with 66 and cruzain [54]. If using docking pose, asking permission to [54].

Figure 23

(a) Lead compounds adapted from [56]; (b)Additive studies performed by Gomes et al. [57]; (c)Test in vivo of similar compounds performed by Ndao et al. [58].

Figure 24

Lead and optimizations obtained by [60].

Figure 25

(a) Compound 79 and its analogue 80; (b) Possible network of interactions regarding compound 80; (c) Possible mechanism of action of covalent inhibitors and CZ.

Figure 26

Compounds synthesized and optimized [73,74].

Figure 27

Representative compounds synthesized Silva et al. [65] and gallinamide A (90) and derived compounds alongside SAR studies [73,74].

Figure 28

Compounds 95–97 and the compounds synthesized in an attempt of activity optimization [69,70].

Figure 29

Hit compounds described in the reference [71].

Figure 30

Compounds 103 to 107 and important parameters related to their activity [4,83,84].

Figure 31

Molecule 103 in the active site post-docking carried out by [83]. There are π-stacking interactions between Tyr₁₂₃ and His_1na with molecule 103, which facilitates the nucleophilic attack of Cys₁₅₃ on carbon 3, with the subsequent leave of bromine. 103 possible interactions with PfGAPDH, as shown in docking studies [4].

Figure 32

Studies performed by Ettari et al. [89].

Figure 33

Hit compounds synthesized by Previti et al. [15].

Figure 34

Compounds obtained, according to references [77,92].

Figure 35

Figure showing compound 122 bound to proteosome in 3d and 2d. Adapted from [78,79].

Figure 36

Best results obtained by [78,79].

Figure 37

Possible mechanism of action of peptide boronates inhibitors. Adapted from [78,79].

Figure 38

Compounds investigated in references [82,101].

Figure 39

Specific differences between hFKBP (blue) and PfFKBP (orange), adapted from Bianchin et al. [89].

Figure 40

Molecules from Atack et al. [91].