Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1H)‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions

Abstract

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

“…brucei growth at an IC 50 of 3.2 μM. However, values in this range are typical of antitrypanosomal compounds in early development …”

“…However, values in this range are typical of antitrypanosomal compounds in early development. [30][31][32] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Compound 4, which features a C-ring methyl sulfonyl, was distinct from the rest of the library by virtue of its disubstituted ortho-trifluoromethyl toluene B-ring. It is important to note that the hit compound from our original screen of the Pathogen Box (1) also featured an ortho-disubstitution pattern.…”

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

“…In parallel, other series have been prepared with the aim of optimizing 2-substituted quinolines with similar biological properties [ 64 , 65 , 66 , 67 ]. Moreover, quinoline-2-one derivatives exhibited in vitro antileishmanial activity in the range from 1 to 15 µM [ 68 , 69 , 70 , 71 ].…”

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

“…Considering the urgent need to develop therapeutic alternatives that target both stages of trypanosomiasis, a partnership between Sanofi and Drug for Neglected Diseases initiative (DNDi) has led to the approval of fexinidazole ( Figure 1) as an alternative therapeutic armament for tackling both stage 1 and 2 HAT [1,20]. However, the ever-growing concern regarding resistance against clinically approved drugs, and the potential for an epidemic outbreak, has resulted in several campaigns focused on identifying new compounds with novel modes of action to prevent and control trypanosomal infections [21][22][23]. Chalcones are open-chain flavonoids, which feature a characteristic three carbon α,βunsaturated carbonyl system [24,25].…”