Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Abstract

To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

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

“…brucei brucei trypomastigote strain and a NTR‐overexpressing strain (Table ). The results were compared with those obtained for the initial hit . The latter is clearly bioactivated by the trypanosomal NTR, being 4.5‐fold more active against the strain overexpressing the NTR than the wild type, whereas 21 is only 1.3 times more active on the strain overexpressing the NTR.…”

“…3‐Bromo‐8‐nitroquinolin‐2(1 H )‐one was prepared in three steps, as presented in Scheme . Nitration of 2‐chloroquinoline mainly led to the intermediate 2‐chloro‐8‐nitroquinoline, which was transformed in a second step into the corresponding lactam, according to a previously reported procedure .…”

“…The redox potentials of the new compounds bearing an aryl group at position 3 ranged between −0.53 and −0.59 V, higher than for the initial hit (−0.45 V) but similar to that of 8‐nitroquinolin‐2(1 H )‐one (−0.54 V). As previously noted in the studied series, the O ‐methylation of compound 21 to give 24 , is responsible for an important decrease in the redox potential value from −0.56 to −0.93 V. This shift is mainly due to the removal of the intramolecular hydrogen bond between the lactam function and the nitro group. It can be concluded that the introduction of a phenyl ring at the position 3 of the scaffold has no significant impact on the redox potential of the studied series but that it allows access to novel antitrypanosomal molecules that display lower reduction potential than the initial hit with the same level of efficacy.…”

“…Pharmacomodulation studies at position 4 of this scaffold were then realised . Recently, we described a comprehensive electrochemistry‐guided study of this pharmacophore and the development of a computational model able to predict the redox potentials of each molecule in the series . Thus, a new antikinetoplastid hit molecule was identified (Figure ).…”

“…[20,21] Recently,w ed escribed ac omprehensive electrochemistry-guided study of this pharmacophore andt he development of ac omputational model able to predict the redox potentials of each molecule in the series. [22] Thus, an ew antikinetoplastid hit molecule was identified ( Figure 3). This molecule wasn ot genotoxic in ac ometa ssay and was selectively bioactivated by type 1N TRs of L. donovani and T. brucei brucei.…”