Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds

Abstract

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.

Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

“…As aforementioned, the protein O97209 (UniProt) bearing Lmj_04_BRCT was described to be involved in L. major infectivity and treatment resistance [ 8 ]. There are multiple examples of targeting individual essential parasite proteins, such as Hsp90 [ 30 ], L. major Pteridine reductase 1 (LmPTR1) [ 31 ], or Leishmania arginase in order to kill the parasite minimizing the harm to the host cell [ 22 , 32 , 33 ]. Therefore, we decided to use our generated models to perform virtual screening and assays to find possible inhibitors of this important domain in L. major .…”

Free Radical Scavenging and Cytotoxic Activities of Substituted Pyrimidines

“…The high activity shown by analogue 26 is due to the positional change of dihydroxyl groups present an aromatic moiety (Table 1). Literature reports have also shown that the phenolic hydroxyl group is responsible for the antioxidant function [21,24] (Figure 3). Compound 1 is the second most potent derivative among the series, containing 4-hydroxy-3,5-dimethoxy groups with IC 50 of value 55.6 ± 2.1 µM, with corresponding 91.58% radical scavenging activity (Tables 1 & 2).…”

“…Besides their anti-tumor action, pyrimidine derivatives have also been found to possess additional biological activities including antibacterial, anti-folate, antibiotic, anti-HIV, anti-fungal, antimycobacterial, anti-leishmanial were also found to inhibit tumor necrotic factor alpha (TNF-α) production and as potent inhibitors of urease enzyme [17][18][19][20][21]. Herein, we report the free radical scavenging activities of a new library of pyrimidine derivatives to evaluate their potential against free radical sustained cancer cell proliferation.…”

Diversification Via Coupling Reactions and Biological Activities of Pyrimidine Derivatives

“…In 2020, Huseyin Istanbullu and colleagues conducted a study on synthesizing and designing novel thiazole pyrimidine derivatives and evaluated their antileishmanial activity against Leishmania species in vitro. [74] The researchers found four synthesized compounds to have both low cytotoxicity and significant antileishmanial activity against the promastigote forms of the parasite, indicating their potential as therapeutic agents. The study included molecular docking experiments, molecular dynamics stimulation, and the in vitro evaluation.…”