Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents

Tarpley, Reid S.; Rugel, Anastasia R.; López, Analía; Menard, Travis; Guzman,; Taylor, Alexander B.; Cao, Xiaoguang; Chevalier, Frédéric D.; Anderson, Timothy J.; Hart, P. John; LoVerde, Philip T.; McHardy, Stanton F.

doi:10.1021/acsmedchemlett.8b00257

Cited by 22 publications

(40 citation statements)

References 36 publications

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“…Oxamniquine derivatives were designed and synthesized by the Center for Innovative Drug Discovery (CIDD) utilizing a structure-based drug design approach using X-ray crystallographic structural data and structure-activity relationship data based on the schistosomicidal efficacy of the derivatives in vitro. The synthesis of the CIDD-0072229 chemical series was previously published [37]. The synthesis used to access CIDD-0149830, along with all supporting analytical data is provided in the supporting information (S1 Table).…”

Section: Compound Design and Oxa Derivativesmentioning

confidence: 99%

“…Compound CIDD-0066790 (compound 12a in [37] has a stereo center at the C3 carbon of the piperidine ring. We modelled SULT-OR interactions with its R-enantiomer, CIDD-0072229, since it had shown maximal worm killing activity.…”

Section: Modelling Of the Cidd-0072229 Interaction With Sult-ormentioning

confidence: 99%

“…Compounds derived from the structural data of OXA in the SmSULT-OR active site were designed, synthesized and initially tested in vitro for worm killing against OXA sensitive S. mansoni adult male worms [37]. Of >300 OXA derivatives prepared and tested, 16 demonstrated over 70% worm killing against S. mansoni in vitro ( [37], this study). Fig 1 and Table 1 show the in vitro killing of S. mansoni.…”

Section: Oxa Derivative In Vitro Screenmentioning

confidence: 99%

“…3, 4-dichloro vs. 2-fluoro-4-trifluoromethyl). Our previous SAR studies on these compounds clearly showed that various electron-withdrawing substituents on the benzyl side chain were preferred for antischistosomal activity [37]. CIDD-0149830 is from the 3, 3-disubstitutied pyrrolidine series, wherein the 3-indole methyl substituent resides on the pyrrolidine nitrogen and the 3-CF 3 -benzyl group is bonded to the C-3 carbon of the pyrrolidine.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

“…Computational modelling was applied to derive a model of the CIDD-0072229 interaction with SmSULT-OR. We used the binding site of SmSULT-OR sourced from the complex with CIDD-000773 [37] CIDD-0072229 binds within the interior of the active site filling contacts from catalytic residues through α-helices α2, α11 and α12 [24]. Superposition of the complex over the crystal structure with S-OXA revealed a nearly complete overlap of CIDD-0072229 over the space occupied by S-OXA (Fig 5A and 5B) [45].…”

Section: Computational Modelling Of Cidd-0072229 In the Binding Pockementioning

confidence: 99%

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An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

et al. 2020

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Currently there is only one method of treatment for human schistosomiasis, the drug praziquantel. Strong selective pressure has caused a serious concern for a rise in resistance to praziquantel leading to the necessity for additional pharmaceuticals, with a distinctly different mechanism of action, to be used in combination therapy with praziquantel. Previous treatment of Schistosoma mansoni included the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The oxamniquine activating enzyme was identified as a S. mansoni sulfotransferase (SmSULT-OR). Structural data have allowed for directed drug development in reengineering oxamniquine to be effective against S. haematobium and S. japonicum. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxamniquine, our structure-based drug design approach produced a robust SAR program that tested over 300 derivatives and identified several new lead compounds with effective worm killing in vitro. Previous studies resulted in the discovery of compound CIDD-0066790, which demonstrated broad-species activity in killing of schistosome species. As these compounds are racemic mixtures, we tested and demonstrate that the R enantiomer CIDD-007229 kills S. mansoni, S. haematobium and S. japonicum better than the parent drug (CIDD-0066790). The search for derivatives that kill better than CIDD-0066790 has resulted in a derivative (CIDD-149830

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Section: Compound Design and Oxa Derivativesmentioning

confidence: 99%

Section: Modelling Of the Cidd-0072229 Interaction With Sult-ormentioning

confidence: 99%

Section: Oxa Derivative In Vitro Screenmentioning

confidence: 99%

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Section: Computational Modelling Of Cidd-0072229 In the Binding Pockementioning

confidence: 99%

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An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

et al. 2020

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Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis**

Buchter

Ong

Mouvet

et al. 2020

Chemistry A European J

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Schistosomiasis is ad iseaseo fp overty affecting millionso fp eople. Praziquantel (PZQ),w ith its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derivedfrom oxamniquine (OXA), an old antischistosomald rug:f errocene-containing (Fc-CH 2-OXA),r uthenocene-containing (Rc-CH 2-OXA) and benzene-containing (Ph-CH 2-OXA) OXA derivatives. These derivatives showed excellent in vitro activity againstb oth Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducteda dditional in-depthp reclinical studiesa nd report in this investigation on metabolic stability studies, in vivos tudies on S. haematobium and juvenile S. mansoni,c omputational simulations,a nd formulation development. Molecular dynamicss imulations supportedt he in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reasonw hy the promising in vitro activity did not translate into in vivo activityo nS. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as aw ay to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability,t or each an active concentration in the microenvironment of the parasite.

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GNN‐DDAS: Drug discovery for identifying anti‐schistosome small molecules based on graph neural network

Zeng,

Feng,

et al. 2024

J Comput Chem

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Schistosomiasis is a tropical disease that poses a significant risk to hundreds of millions of people, yet often goes unnoticed. While praziquantel, a widely used anti‐schistosome drug, has a low cost and a high cure rate, it has several drawbacks. These include ineffectiveness against schistosome larvae, reduced efficacy in young children, and emerging drug resistance. Discovering new and active anti‐schistosome small molecules is therefore critical, but this process presents the challenge of low accuracy in computer‐aided methods. To address this issue, we proposed GNN‐DDAS, a novel deep learning framework based on graph neural networks (GNN), designed for drug discovery to identify active anti‐schistosome (DDAS) small molecules. Initially, a multi‐layer perceptron was used to derive sequence features from various representations of small molecule SMILES. Next, GNN was employed to extract structural features from molecular graphs. Finally, the extracted sequence and structural features were then concatenated and fed into a fully connected network to predict active anti‐schistosome small molecules. Experimental results showed that GNN‐DDAS exhibited superior performance compared to the benchmark methods on both benchmark and real‐world application datasets. Additionally, the use of GNNExplainer model allowed us to analyze the key substructure features of small molecules, providing insight into the effectiveness of GNN‐DDAS. Overall, GNN‐DDAS provided a promising solution for discovering new and active anti‐schistosome small molecules.

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Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents

Cited by 22 publications

References 36 publications

An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis**

GNN‐DDAS: Drug discovery for identifying anti‐schistosome small molecules based on graph neural network

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