Pyrimido[5,4-d]pyrimidine-Based Compounds as a Novel Class of Antitrypanosomal and Antileishmanial Agents

Abstract

Sleeping sickness and leishmaniasis are neglected tropical diseases that threaten millions of people. The currently available therapies present several limitations, including high toxicity, lack of efficacy, and emerging drug resistance, prompting a search for novel therapeutic agents. In this work, we designed, synthesized, and in vitro evaluated the activity of new pyrimido­[5,4-d]­pyrimidines against Trypanosoma brucei and Leishmania infantum (promastigote and amastigote forms). The cytotoxicity of the compounds against the THP1 cell line was also assessed. Most tested compounds presented low micromolar activity against T. brucei with IC50 values in the range between 0.9 and 13.4 μM, and one compound also showed activity against L. infantum (IC50 = 3.13 μM). Several molecules presented a selectivity index higher than 10. The most active compound against booth parasites is derivative 4c, with IC50 = 0.94 μM (SI > 107) against T. brucei and IC50 = 3.13 μM (SI > 32) against L. infantum. This data enabled the identification of a new promising molecular scaffold for developing a novel class of antitrypanosomal and antileishmanial agents.

A Tandem Reaction in the Synthesis of New 4,8‐Disubstituted‐pyrimido[5,4‐d]pyrimidine Derivatives

“…The compounds of interest, 5 , have specific R, R 1 groups at heterocycle's positions 4 and 8 (Scheme 2). The starting reagents 2 , used in this study (Scheme 3), were synthesized following a synthetic approach and procedures previously developed by the research group [20,24–26] that allow the introduction of the aimed R group at position 8.…”

“…[23] Recently, three new derivatives 3 (R' = NH 2 ) were obtained from the reaction of 2 with piperidine, in ethanol, at 80 °C in variable yields. [24] All the results collected so far from these reactions show that the reaction conditions to convert 2 into 3 are very sensitive and delicate, depending largely on the R' groups.…”

“…The one-pot synthesis was also followed by 1 In this work, we describe an efficient Dimroth rearrangement of compounds 2 (R' = NH 2 ) and 18 in DMSO by the action of piperidine. Previously, Dimroth rearrangement of 2 was performed in ethanol using piperidine (R' = NH 2 ) [24] or hydrochloric acid (R' = OBn), [21] but when these reaction conditions were applied to derivatives 2 (R=NHCOR 2 ) [23] complex mixtures were obtained. Complex mixtures were also obtained when sulfuric acid or aqueous sodium hydroxide were used.…”

“…Compounds 3 (R’=NHCOR 2 ) were later obtained from 6‐amidinopurines 4 in ethanol, in the presence of piperidine, under reflux (Scheme 1). [23] Recently, three new derivatives 3 (R'=NH 2 ) were obtained from the reaction of 2 with piperidine, in ethanol, at 80 °C in variable yields [24] …”

“…In our drug discovery and development program, we design new derivatives of pyrimidopyrimidines with pharmacological interest having structure 5 (Scheme 2) [24] that have compounds 3 as intermediates. A new synthetic strategy was planned to synthesise compounds 5 from compounds 2 (Scheme 2).…”