CF₃‐Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine‐Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase

3区 · 化学

Article

作者: Olotu, Fisayo A. ; Soliman, Mahmoud ; Salifu, Elliasu Y. ; Agoni, Clement ; Munsamy, Geraldene

AbstractThe quest for reliable dihydroorotate dehydrogenase (DHODH) inhibitors has engendered the discovery of potential therapeutic compounds at different stages of clinical trials. Although promising, high attrition rates and unfavorable bioactivities have limited their drug developmental progress. A recent structural modification of DSM265, a triazolopyrimidine‐based inhibitor, yielded DSM421, derived by the substitution of the SF5‐aniline group on DSM265 with a CF3‐pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF3‐pyridinyl group leaves us with a curiosity to investigate underlying ligand‐binding mechanisms and dynamics using computational methods. Presented in this study are insights that clearly explain the effects of structural SF5‐aniline→CF3‐pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF3‐pyridinyl group induced an optimal and stabilized positioning of DSM421 within the binding pocket, allowing for steady and strong intermolecular interactions which favored its stronger binding affinity as estimated and correlated with bioactivity data. These interactions consequently induced a pronounced stabilization of the structural conformation of pfDHODH by restricting residue motions, which possibly underpinned its enhanced inhibitory activity relative to DSM265. Active site interactions of the CF3‐pyrinidyl group with residues Ser236, Ile237, and Phe188 characterized by strong π–π stacking and halogen interactions also stabilized its positioning which altogether accounted for its enhanced inhibitory prowess towards pfDHODH. On the contrary, fewer and weaker interactions characterized DSM265 binding which could explain its relatively lower binding affinity. Findings will facilitate the design of novel pfDHODH inhibitors with enhanced properties.

2019-09-01·Journal of Pharmacological and Toxicological Methods

Increased stress associated with head-out plethysmography testing can exacerbate respiratory effects and lead to mortality in rats

Article

作者: Mirsalis, Jon ; Rao, Mohan ; Mittelstadt, Scott W ; Segreti, Jason A ; Rossignol, Emilie ; Moehrle, Joerg J ; Parman, Toufan ; Marsh, Kennan C ; Lynch, James J ; Ottinger, Sean E ; Van Vleet, Terry R

INTRODUCTIONDSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750 mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy.METHODSPotential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated.RESULTSRespiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-h post-dosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A₃ receptor (which is associated with bronchoconstriction).DISCUSSIONThe generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular effects, thus artifactually resulting in moribundity and mortality in rats. Care should be taken when choosing whether to use head-out versus whole-body plethysmography chambers during respiratory function testing in animals.

2016-12-09·ACS Infectious Diseases2区 · 医学

A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

2区 · 医学

Article

作者: Sreekanth Kokkonda ; Kennan Marsh ; Anne Marie Zeeman ; John White ; Margaret A. Phillips ; Werner Kaminsky ; Maria Santos Martinez ; Pradipsinh K. Rathod ; Susan A. Charman ; Rintis Noviyanti ; Michael Campbell ; Jeremy N. Burrows ; Grennady Wirjanata ; Emilie Rossignol ; Xiaoyi Deng ; Farah El Mazouni ; Kigbafori Silue ; Santiago Ferrer Bazaga ; Jutta Marfurt ; Ric N. Price ; Diana R. Tomchick ; Michael J. Palmer ; David M. Shackleford ; Francis C K Chiu ; Krishne Manjalanagara ; Benjamin Blasco ; Maria Lafuente-Monasterio ; Kakali Rani Rudra ; David Waterson ; Maria Belen Jimenez-Diaz ; Karen L. White ; Thomas Rueckle ; Iñigo Angulo-Barturen ; Dave Matthews ; Clemens Kocken ; Didier Leroy

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF₅-aniline moiety of DSM265 with a series of CF₃-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

100 项与 DSM-421 相关的药物交易

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