article · Journal of Enzyme Inhibition and Medicinal Chemistry
New spiro-piperidine derivatives have been synthesised through an environmentally friendly, one-pot process using ionic liquids. When evaluated in laboratory tests against both promastigote and amastigote stages of Leishmania major, most of these compounds demonstrated promising antileishmanial properties that outperformed the standard drug miltefosine. Two primary candidates, designated 8a and 9a, showed sub-micromolar potency, achieving half-maximal inhibitory concentrations of 0.89 micromolar and 0.50 micromolar, compared to 8.08 micromolar for miltefosine. Reversal assays using folic and folinic acids indicated that the compounds act via an antifolate mechanism by targeting the enzymes DHFR and PTR1. Furthermore, testing on VERO cells revealed that the leading molecules possess greater selectivity and an improved safety profile relative to miltefosine. Molecular docking and dynamic simulations confirmed stable binding to the parasite enzyme target.
Leishmaniasis requires more effective and less toxic treatments, as current medications like miltefosine can present safety and efficacy concerns. Developing potent compounds that specifically disrupt parasite enzyme function while sparing host cells offers a pathway towards safer, more dependable therapeutics. Demonstrating higher potency and improved selectivity in laboratory tests is an important step in discovering alternative treatments for parasitic infections.
This research is at an early, laboratory-based discovery stage. The synthesised molecules represent prospective chemical scaffolds for pharmaceutical developers seeking to design new antileishmanial drugs. While the compounds outperform miltefosine in cell culture safety and potency, extensive preclinical animal testing, formulation development, and clinical evaluation will be required before any commercial or therapeutic use can be realised.
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New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The <i>in vitro</i> antileishmanial activity against <i>Leishmania major</i> promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds <b>8a</b> and <b>9a</b> exhibited sub-micromolar range of activity, with IC<sub>50</sub> values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds <i>via</i> folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism <i>via</i> targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of <b>8a</b> and <b>9a</b> against <i>Lm</i>-PTR1 rationalised the observed <i>in vitro</i> activities. Molecular dynamics simulations confirmed a stable and high potential binding to <i>Lm</i>-PTR1.
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DOI: 10.1080/14756366.2022.2150763
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