Unravelling the Structure of Peroxides with Antiparasitic Activity: The Relative Impact of a Trioxolane or a Tetraoxane Pharmacophore on the Overall Molecular Structure

Article

作者: Paixão, José A. ; Amado, Patrícia S. M. ; Fausto, Rui ; Cristiano, Maria L. S. ; Jesus, A. J. Lopes

AbstractPlasmodium falciparum artemisinin‐resistance boosted the quest for novel plasmodial “fast killers,” uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4‐trioxolane (1) and 1,2,4,5‐tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X‐ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE‐B3LYP/6‐31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane‐adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C−H⋅⋅⋅O H‐bonds in 1 connect an adamantyl C−H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C−H groups. C−H⋅⋅⋅O and C−H⋅⋅⋅π H‐bonds define the molecular packing of 2, while C−H⋅⋅⋅H−C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.

2022-03-01·Environmental Research2区 · 环境科学与生态学

Atmospheric concentrations of polychlorinated biphenyls, brominated flame retardants, and novel flame retardants in Lagos, Nigeria indicate substantial local sources

2区 · 环境科学与生态学

Article

作者: Olusegun Ayejuyo ; Mohamed Abou-Elwafa Abdallah ; William A. Stubbings ; Stuart Harrad ; Olumide Emmanuel Akinrinade ; Rose Alani

Polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs) like polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), and novel flame retardants (NFRs) like decabromodiphenyl ethane (DBDPE) are ubiquitous environmental pollutants. Despite this, little is known about their concentrations in outdoor air in the African continent. To address this knowledge gap, concentrations of BFRs, NFRs, and PCBs were measured in outdoor air at 8 sites located within the metropolitan area of Lagos, Nigeria. Concentrations of ∑₈BDEs, ∑HBCDD, ∑₇NFRs and ∑₈PCBs were: 21-750 (median = 100) pg/m³, <12-180 (median = < 12) pg/m³, 34-900 (median = 300) pg/m³ and 85-460 (median = 300) pg/m³, respectively. Decabromodiphenyl ether (BDE-209, range: <16-620 pg/m³, median = 71 pg/m³) and DBDPE (range: <37-890 pg/m³, median = 280 pg/m³) were the dominant BFRs detected, while the non-Arochlor PCB 11 (range: 49-220 pg/m³, median = 100 pg/m³) was the dominant PCB. To the authors' knowledge, these are the first data on the non-Arochlor PCB 11 in outdoor air in Africa. In general, concentrations of all target contaminants in this study were within the range reported elsewhere in Africa and worldwide. Likely due to the tropical climate of Lagos, no seasonal variation in concentrations was discernible for any of the target contaminants. While concentrations of PBDEs and some NFRs were correlated with population density, concentrations of PCBs appear more impacted by leaks from electrical transformers and for PCB 11 to proximity to activities like textile factories that produce and use dyes.

2021-11-01·Medicinal Research Reviews1区 · 医学

Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies

1区 · 医学

Review

作者: Cristiano, Maria L. S. ; Amado, Patrícia S. M. ; O'Neill, Paul M. ; Woodley, Christopher M.

AbstractArtemisinin combination therapies (ACTs) have been used as the first‐line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi‐synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme‐mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide‐based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2‐dioxanes, 1,2,4‐trioxanes, 1,2,4‐trioxolanes, and 1,2,4,5‐tetraoxanes. Two of these classes, the 1,2,4‐trioxolanes (arterolane and artefenomel) and the 1,2,4,5‐tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2‐dioxane, Arteflene, and 1,2,4‐trioxanes fenozan‐50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.

100 项与 E-209 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
疟疾	临床前	日本	Eisai Co., Ltd.	-
疟疾	药物发现	英国	Liverpool School of Tropical Medicine	-
疟疾	药物发现	英国	The University of Liverpool	-