The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents

Linciano, Pasquale; Pozzi, Cecilia; Tassone, Giusy; Landi, Giacomo; Mangani, Stefano; Santucci, Matteo; Luciani, Rosaria; Ferrari, Stefania; Santarem, Nuno; Tagliazucchi, Lorenzo; Cordeiro-da-Silva, Anabela; Tonelli, Michele; Tondi, Donatella; Bertarini, Laura; Gul, Sheraz; Witt, Gesa; Moraes, Carolina B.; Costantino, Luca; Costi, Maria Paola

doi:10.1016/j.ejmech.2023.115946

Cited by 4 publications

(1 citation statement)

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“…Monocyclic and bicyclic aromatic systems such as pyrimidines, pteridines, quinolines, pyrrolo-pyrimidines, benzimidazoles, and benzothiazoles, mimicking the substrate pterin moiety, were extensively studied as molecular scaffolds for the design of Tb PTR1 and Tb DHFR inhibitors. ,− Also, the antimalarial drug cycloguanil (Cyc) (Figure a), featured by a dihydrotriazine core, was found to target Tb PTR1 besides Plasmodial and Trypanosoma DHFR . Interestingly, Cyc exhibited a superior affinity for Tb DHFR ( K i = 256 nM) than Tb PTR1 (IC 50 = 31.6 μM) and a low antiparasitic effect against T.…”

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Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents

Francesconi,

Rizzo,

Pozzi

et al. 2024

ACS Infect. Dis.

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Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (K i = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.

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