Summary of project PR002795
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002795. The data can be accessed directly via it's Project DOI: 10.21228/M8CK2X This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002795 |
| Project DOI: | doi: 10.21228/M8CK2X |
| Project Title: | Stereochemistry-Driven Design and Synthesis of Tadalafil Analogues as Antiplasmodial Agents |
| Project Summary: | Analogues of tadalafil, an FDA-approved inhibitor of human phosphodiesterase 5 have been reported to block Plasmodium falciparum growth in vitro. In this study, we synthesized 56 new tadalafil analogues with specific stereochemistry; some of the novel analogues showed potent antiplasmodial activity at nanomolar concentrations and high selectivity in vitro. Compound 33 demonstrated the highest potency, with an IC50 of 80 nM against cultured parasites and an IC50 > 20 µM on human HeLa cells, resulting in a selectivity index >250. Most active compounds showed stereospecific activity favoring the cis isomer with a 6R, 12aR configuration. We demonstrate that conformational and spatial orientation play a more critical role than lipophilicity in determining the activity of these compounds. Metabolomic profiling revealed that several tadalafil analogues strongly affect hemoglobin catabolism; yet principal component analysis (PCA) grouped them separately, suggesting subtle differences in their antiplasmodial mechanisms. Further work will be needed to elucidate their precise mode of action, and future structural optimization will be necessary towards development of tadalafil analogues as antimalarial treatments. |
| Institute: | Pennsylvania State University |
| Department: | Biochemistry and Molecular Biology |
| Laboratory: | Manuel Llinás |
| Last Name: | Rangel |
| First Name: | Gabriel |
| Address: | 491 Pollock Road, University Park, PA, 16802, USA |
| Email: | grangel0955@gmail.com |
| Phone: | 8148673527 |
Summary of all studies in project PR002795
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004424 | Stereochemistry-Driven Design and Synthesis of Tadalafil Analogues as Antiplasmodial Agents | Plasmodium falciparum | Pennsylvania State University | MS | 2025-12-29 | 1 | 25 | Uploaded data (1G)* |
