Lipophilic conformationally constrained spiro carbocyclic 2,6‐diketopiperazine‐1‐acetohydroxamic acid analogues as trypanocidal and leishmanicidal agents: An extended SAR study

Abstract

We have previously described a number of lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine (2,6-DKP)-1-acetohydroxamic acids as potent antitrypanosomal agents. In this report, we extend the SAR analysis in this class of compounds with respect to in vitro growth inhibition of Trypanosoma and Leishmania parasites. Introduction of bulky hydrophobic substituents at the vicinal position of the basic nitrogen atom in the spiro carbocyclic 2,6-DKP ring system can provide analogues which are potently active against bloodstream form Trypanosoma brucei and exhibit significant activities toward Trypanosoma cruzi epimastogotes and Leishmania infantum promastigotes and intracellular amastigotes. In particular, compounds possessing a benzyl or 4-chlorobenzyl substituent were found to be the most active growth inhibitors, with activities in the low nanomolar and low micromolar ranges for T. brucei and L. infantum, respectively. The benzyl-substituted (S)-enantiomer was the most potent derivative against T. brucei (IC = 6.8 nm), T. cruzi (IC = 0.21 μm), and L. infantum promastigotes (IC = 2.67 μm) and intracellular amastigotes (IC = 2.60 μm). Moreover, the (R)-chiral benzyl-substituted derivative and its racemic counterpart displayed significant activities against L. donovani. Importantly, the active compounds show high selectivity in comparison with two mammalian cell lines.

Scaffold hybridization strategy towards potent hydroxamate-based inhibitors ofFlaviviridaeviruses andTrypanosomaspecies

“…Rational designtheoretical calculations Previous studies by our group have resulted in compounds carrying metal chelating moieties that demonstrated a highly promising inhibition capacity against either pathogenic viruses, including influenza and HCV, 56 or parasites of the Trypanosoma genus. 57,58 The two above-mentioned series of analogues, although structurally diverse, were based on rational incorporation of metal chelating moieties on scaffolds with pronounced drug-likeness, such as the combination of flutimide with the indole system (I) or incorporation of the acetohydroxamic acid moiety on a 2,6-diketopiperazine (2,6-DKP) scaffold (II) (Fig. 3).…”

In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum

“…Thus, compound 15 displays itself as a promising starting point for further development of potent agents against Leismania infantum parasites. One important additional aspect that will have to be evaluated in further development of this hit compound is also to determine its influence on the mammalian cells [ 30 ].…”

Novel 2,6-diketopiperazine-derived Acetohydroxamic Acids as Promising Anti- Trypanosoma Brucei Agents

“…Lancet 391, 144-154. [6] European Medicines Agency recommends fexinidazole, the first all-oral treatment for sleeping sickness. https://www.dndi.org/2018/media-centre/pressreleases/).…”

“…Some of these derivatives (III-IV, Figure 1) showed submicromolar trypanocidal activities in vitro; in particular the adamantane analogue III (IC 50 =0.33 μΜ) gave 400-and 21-fold increases in antitrypanosome potency compared to amantadine and rimantadine, respectively. 6 In our earlier works we communicated the trypanocidal properties of some nitrogen-containing adamantane derivatives (amines or not). 7,8 Among them, compounds V-VII (Figure 1) possessed considerable activities in vitro against T. brucei.…”

“…Unfortunately, these compounds were only marginally active against T. brucei parasite. Yet, compounds VIIIa and VIIIb as well as other lipophilic spiro carbocyclic 2,6-DKPs represent useful scaffolds that can be transformed into potent trypanocidal agents, with single nanomolar to submicromolar activities, by introducing an acetohydroxamic acid moiety to their imidic nitrogen [5,6]. Thus, we produced a series of lipophilic, constrained spiro carbocyclic 2,6-diketopiperazine-1acetohydroxamic acid derivatives (Fig.…”