Structural Insights into the Development of Cycloguanil Derivatives as <i>Trypanosoma brucei</i> Pteridine-Reductase-1 Inhibitors

Landi, Giulia; Linciano, Pasquale; Borsari, Chiara; Bertolacini, Claudia P; Moraes, Carolina Borsoi; Cordeiro-da-Silva, Anabela; Gul, Sheraz; Witt, Gesa; Kuzikov, Maria; Costi, Maria Paola; Pozzi, Cecilia; Mangani, Stefano

doi:10.1021/acsinfecdis.8b00358

Cited by 16 publications

(22 citation statements)

References 50 publications

(99 reference statements)

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“…Landi et al [69] exploited cycloguanil as a scaffold for the development of novel pteridine-reductase-1 (PTR1) inhibitors. The elucidation of the binding mode supported the rational design of novel 2,4-diamino-1,6-dihydrotriazine derivatives, thus identifying two new potent PTR1 inhibitors as a valuable starting point for the development of dual PTR1 and dihydrofolate reductase (DHFR) inhibitors with antiparasitic activity.…”

Section: Highlighted By Simona Collinamentioning

confidence: 99%

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

et al. 2019

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Section: Highlighted By Simona Collinamentioning

confidence: 99%

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

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“…It is interesting to understand how PYR and CYC, despite their substantial structural similarity, show a significantly different inhibition potency. Accordingly, in the present work, we analyzed the structural basis of CYC versus PYR inhibition of TbPTR1 and then explored some CYC analogues (1-6) with a modified substitution pattern to understand how targeted structural modification of CYC can influence the inhibition ability towards both TbPTR1 and TbDHFR [20,22,35]. The structural comparison between the binding mode of PYR and CYC in TbPTR1 and TbDHFR led to key insights for the future design of more promising dual inhibitors for HAT therapy.…”

Section: Introductionmentioning

confidence: 99%

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

et al. 2021

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Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

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“…The TbPTR1 inhibitors developed to date were conceived as substrate-competitive inhibitors and are based on a wide variety of scaffolds, including 2,4-diaminopteridine (Dawson et al, 2006;Tulloch et al, 2010), quinazoline (Dawson et al, 2010), 2,4-diaminopyrrolopyrimidine (Tulloch et al, 2010), chromone (Borsari et al, 2016;Di Pisa et al, 2017), 2-aminothiadiazole (Linciano et al, 2017), 2-aminobenzimidazole (Mpamhanga et al, 2009), triazine (Tulloch et al, 2010), 1,6-dihydrotriazine (Landi et al, 2019) and 2-aminobenzothiazole (Linciano et al, 2019). More than 60 crystal structures of TbPTR1-inhibitor complexes have now been deposited in the Protein Data Bank (PDB), clarifying the key binding interactions that occur inside the catalytic cavity (Pozzi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

Landi

Linciano

Tassone

et al. 2020

Acta Cryst Sect D Struct Biol

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The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monocyclic and bicyclic aromatic systems have been proposed as inhibitors of T. brucei PTR1 (TbPTR1); nevertheless, the size of the catalytic cavity allows the accommodation of expanded molecular cores. Here, an innovative tricyclic-based compound has been explored as a TbPTR1-targeting molecule and its potential application for the development of a new class of PTR1 inhibitors has been evaluated. 2,4-Diaminopyrimido[4,5-b]indol-6-ol (1) was designed and synthesized, and was found to be effective in blocking TbPTR1 activity, with a K i in the low-micromolar range. The binding mode of 1 was clarified through the structural characterization of its ternary complex with TbPTR1 and the cofactor NADP(H), which was determined to 1.30 Å resolution. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions. The binding mode of 1 was compared with those of previously reported bicyclic inhibitors, providing new insights for the design of innovative tricyclic-based molecules targeting TbPTR1.

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Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors

Cited by 16 publications

References 50 publications

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

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