Selective Activation Research Articles

Thanatin and vinyl sulfide analogues as narrow spectrum antimicrobial peptides that synergise with polymyxin B

Thanatin is a β-hairpin antimicrobial peptide cyclised by a single disulfide bond that has shown potent broad-spectrum activity towards bacterial and fungal pathogens. Towards Gram-negative species, thanatin acts both by forming trans-membranal pores and inhibiting outer membrane biogenesis by binding to LptA and blocking lipopolysaccharide (LPS) transport. Inspired by previous modifications of thanatin, an analogue was prepared which demonstrated potent but selective activity towards E. coli. Furthermore, this compound was shown to act in synergy with the highly potent FDA-approved lipopeptide antibiotic polymyxin B, which engages LPS at the cytoplasmic membrane. Four analogues of thanatin in which the disulfide was substituted for vinyl sulfide bridge mimetics were prepared, all of which retained similar secondary structures. Two of these retained substantial potency and selectivity towards E. coli. Importantly, synergy with polymyxin B was also maintained for the lead analogue. The vinyl sulfide potentially offers a facile replacement strategy for labile disulfide bonds and the selective activity and drug synergy of the reported thanatin analogues is promising for the development of narrow spectrum antimicrobials with reduced likelihood of resistance emerging in clinical settings.

Effects of Extrinsic and Intrinsic Motivation on Selective Activation of Shoulder Girdle Muscles During the Barbell Bench Press Exercise

Background/Objectives: This study aimed to investigate the effects of intrinsic and extrinsic motivation on selective muscle activation of the shoulder girdle during the barbell bench press. Specifically, this research focused on how attentional focus on individual muscles, such as the anterior deltoid (AD), pectoralis major (PM), and triceps brachii long (TBL), could influence their electromyographic (EMG) activity during the exercise. Methods: Twelve male participants, with at least five years of strength training experience, performed bench press exercises under two conditions: with extrinsic motivation (no specific focus on muscle activity) and with intrinsic motivation (internal focus on specific muscles). Surface electromyography (sEMG) was used to measure muscle activity during three sets of bench presses at 60% of one repetition maximum (1RM). Participants were instructed to focus on the activation of specific muscles in a randomized sequence. Results: The intrinsic motivation condition significantly increased muscle activation compared to extrinsic motivation. Electromyographic activity of the AD, PM, and TBL muscles was notably higher when participants focused their attention on these muscles. AD activation increased from 71.78 ± 11.13%MVC (extrinsic) to 88.03 ± 8.84%MVC (intrinsic) (p = 0.0019), while PM and TBL activation also demonstrated significant increases under intrinsic focus. Conclusions: The study concludes that intrinsic motivation, or an internal focus on specific muscle activation, can significantly enhance EMG activity in target muscles during the bench press exercise. This finding has important implications for resistance training and rehabilitation, where focused muscle activation can be utilized to improve training outcomes and muscle engagement.

Synthesis and Biological Activity of Tetracyclic Dispiro Core Derivatives of Natural Products Dispirocochlearoids A-C.

Natural products dispirocochlearoids A-C, which are meroterpenoids derived from Ganoderma fungi, feature a 6/6/5/6/6/6 ring system and exhibit selective COX-2 inhibitory activity. Herein, the concise total synthesis of the tetracyclic core structure of dispirocochlearoids A-C was achieved through an aldol reaction/cyclization/deprotection/cyclization cascade sequence. A series of simplified tetracyclic analogues was successfully constructed and their anti-inflammatory activity was further explored, with several tetracyclic analogues (such as compound 8ab) exhibiting strong inhibitory activity against IL-1β expression in lipopolysaccharide-stimulated bone marrow-derived macrophage cells (IC50 = 2.8 μM).

Synthesis and Cytotoxic Activity of Quinazoline-benzofuran Conjugates.

In order to study on structure-activity relationships of benzofurans. Benzofuran is a kind of natural compound widely existing in nature with pharmacological effects. The development of new anticancer benzofuran derivatives has attracted more and more attention. We have introduced an active quinazoline unit into piperazine-substituted benzofuran, prepared a series of quinazoline-benzofuran compounds, and evaluated cytotoxic activity against a panel of human tumor cell lines by MTT assay. 48 novel quinazoline-substituted benzofuran derivatives have been prepared, and in vitro, cytotoxic activity against five human tumor cell lines was evaluated. The results indicated that some quinazoline-benzofuran conjugates showed selective inhibitory activity against tumor cell lines. We have found that compound 14x displayed excellent cytotoxic activity, which could be considered a potential anticancer agent.

Advancement in Heterogeneous Catalysts for the Synthesis of Benzothiazole Derivatives

AbstractBenzothiazole derivatives, a class of heterocyclic compounds, hold significant relevance in medicinal chemistry, materials science, and agrochemicals due to their diverse biological activities and applications. The conventional synthetic routes often involve harsh conditions and generate significant waste, prompting the exploration of more sustainable approaches. This work offers a comprehensive analysis of the developments in the use of heterogeneous catalysts for the production of benzothiazole derivatives, covering research from 2013 onward. Compared to traditional techniques, heterogeneous catalysts provide improved sustainability, efficiency, and recyclability. The review covers many heterogeneous catalysts and discusses their selectivity, recyclability, and catalytic activity. The utilization of heterogeneous catalysts is noteworthy as it facilitates the synthesis process's overall sustainability by allowing for milder reaction conditions, less environmental effect, and easier catalyst separation and recovery. The potential of heterogeneous catalysis in promoting the production of benzothiazole derivatives and satisfying the increasing need for these substances in various industrial applications is also highlighted.

Nanodomain-Enhanced Stable and Multifunctional Probes with Near 100% Quantum Yield for Versatile Biosensing.

The preparation of high quantum yield, stable, and multifunctional fluorescent probes is of great significance in the fields of biomedicine and photoelectric sensing. Here, a triphenylamine-based D-π-A fluorescent molecule (TPA-CN) was designed and prepared, demonstrating a fluorescence quantum yield of 88.84%. With a polystyrene nanosphere as the carrier, TPA-CN was encapsulated inside the nanosphere to form intra-nanosphere confining domains. These nanodomain-enhanced fluorescent nanospheres exhibited a fluorescence quantum yield of 98.21%. Using antigen-antibody specificity and the selective catalytic activity of a bioenzyme, with chloramphenicol as a model target, a dual-signal readout biosensor (in fluorescence and colorimetric modes) was designed for ultrasensitive and instrument-free determination. The detection limit was 24 pg/mL within 30 min in fluorescence mode, 38-fold more sensitive and 10-fold faster than that of enzyme linked immunosorbent assays. The nanodomain-enhanced fluorescent probes and dynamic biosensor provide a robust and versatile solution for public health and environmental monitoring needs.

Synthesis, Characterization, and Biological Investigation of Antimony(III) Halide Complexes With Different Coordination Architectures Constructed From Thiophene Thiosemicarbazones

ABSTRACTIn this study, we report the synthesis, characterization, and biological investigation of antimony(III) halide complexes with various coordination architectures constructed from thiophene thiosemicarbazones. Antimony(III) thiophene‐2‐carbaldehyde thiosemicarbazone complexes (1, 2, 4, and 5) exhibit a square pyramidal geometry, with ligands coordinated to the central antimony atom in two distinct binding modes. In contrast, antimony(III) 2‐acetylthiophene thiosemicarbazone complexes (3, 6, and 7) adopt a seesaw geometry. These complexes (1–7) represent the first reported examples of antimony(III) halide thiosemicarbazone compounds. The unique coordination environments observed in these complexes are of significant importance within the realm of antimony chemistry. These synthesized complexes exhibit different coordination geometries as well as potential biological activities. The antiproliferative activity against the human breast adenocarcinoma (MCF‐7) cell line and antimicrobial activity against Gram‐positive and Gram‐negative bacteria were assessed. Antimony(III) thiophene‐2‐carbaldehyde thiosemicarbazone complexes (1, 2, 4, and 5) showed significant antiproliferative activity with IC50 values ranging from 8.5 to 19.1 μM, while antimony(III) 2‐acetylthiophene thiosemicarbazone complexes (3, 6, and 7) had higher IC50 values. Additionally, the antimony complexes demonstrated selective antimicrobial activity against Gram‐negative bacteria.

Antimicrobial Peptide with a Bent Helix Motif Identified in Parasitic Flatworm Mesocestoides corti

The urgent need for antibiotic alternatives has driven the search for antimicrobial peptides (AMPs) from many different sources, yet parasite-derived AMPs remain underexplored. In this study, three novel potential AMP precursors (mesco-1, -2 and -3) were identified in the parasitic flatworm Mesocestoides corti, via a genome-wide mining approach, and the most promising one, mesco-2, was synthesized and comprehensively characterized. It showed potent broad-spectrum antibacterial activity at submicromolar range against E. coli and K. pneumoniae and low micromolar activity against A. baumannii, P. aeruginosa and S. aureus. Mechanistic studies indicated a membrane-related mechanism of action, and circular dichroism spectroscopy confirmed that mesco-2 is unstructured in water but forms stable helical structures on contact with anionic model membranes, indicating strong interactions and helix stacking. It is, however, unaffected by neutral membranes, suggesting selective antimicrobial activity. Structure prediction combined with molecular dynamics simulations suggested that mesco-2 adopts an unusual bent helix conformation with the N-terminal sequence, when bound to anionic membranes, driven by a central GRGIGRG motif. This study highlights mesco-2 as a promising antibacterial agent and emphasizes the importance of structural motifs in modulating AMP function.

A novel methionyl-tRNA synthetase inhibitor targeting gram-positive bacterial pathogens.

New antibiotics are needed to treat gram-positive bacterial pathogens. MRS-2541 is a novel inhibitor of methionyl-tRNA synthetase with selective activity against gram-positive bacteria. The minimum inhibitory concentrations (MICs) against Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus species range from 0.063 to 0.5 µg/mL. Given orally to mice at 50 mg/kg every 8 hours, MRS-2541 shows sustained plasma levels well above these MICs. In the mouse thigh infection model, MRS-2541 decreased methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes bacterial loads to the same degree as linezolid. MRS-2541 is a promising new antibiotic for development against skin and soft tissue infections.

Selective Metal‐Coordinated Nanodrugs Based on Thiazine Moiety for Anticancer Therapeutics: Spectroscopic, Theoretical, and Molecular Docking Studies

ABSTRACTThe current study involved production, comprehensive structural analysis, and physicochemical characterizing of two distinctive complexes namely, Cu(TBH) and Zn(TBH); TBH donor ligand: N′‐(1‐(3,6‐dihydro‐4‐hydroxy‐2,6‐dioxo‐2H‐1,3‐thiazin‐5‐yl)ethylidene)‐2‐hydroxybenzohydrazide) using a wide range of analytical methods, including elemental analysis, UV–Vis, FT‐IR, and 1HNMR spectrometry, molar conductivity and magnetic susceptibility measurements, and thermal analysis. According to the findings, chelation can occur through O, N, and O donor atoms of monoanionic chelator for generating mono‐nuclear chelates with tetrahedral geometry for Cu (II) and octahedral geometry for Zn (II). The anticarcinogenic ability of TBH chelator and its coordinated compounds against human liver cancer (HepG‐2) was investigated. The Cu(TBH) complex was found to have selective and promising anticancer activity against a liver cancer cell line, with lower IC50 (liver carcinoma cell line) and higher IC50 (normal human cell line) values than other produced compounds and standard drugs. Utilizing DFT computations, the molecular structures of the TBH and its complexes were verified, offering a detailed understanding of their quantum chemical characteristics. A quantitative structure–activity relationship (QSAR) model, which illustrates the association between DFT‐computed descriptors and biological activities pIC50, was also created using multiple linear regression (MLR) on the synthesized compounds as anticancer medicines. Additionally, there are no issues with the produced compounds' oral bioavailability according to (ROF) Lipinski's rule of five. Furthermore, docking studies of the synthesized TBH chelator and its chelates with CDK2 kinase have been performed to validate the biological findings. According to our findings, the novel Cu(TBH) nanodrug exhibits considerable cytotoxic activity, prompting further study into its pharmacological profile and exploring its potential in drug development.

Combined Phase 1/2a Initial Clinical Safety Trials and Proof-of-Concept Assessment of a Novel Antimicrobial Peptide KSL-W Anti-Plaque Chewing Gum.

The effective control of dental plaque is crucial for oral health, given that pathogenic bacteria in plaque are the primary cause of dental caries. Current antimicrobial agents, although effective, disrupt the oral microbiome and lead to oral dysbiosis, hindering efforts to curb dental caries. Novel antimicrobial peptides offer a promising solution due to their selective bactericidal activity against cariogenic bacteria. This study explores the initial safety and efficacy of KSL-W formulated into chewing gum through a Phase 1 and 2a clinical trial. The combined trial, approved by the FDA, follows a double-blind, randomized, placebo-controlled design. Phase 1 assessed safety with single doses (2-100 mg), whereas Phase 2a explored both safety and proof of concept in reducing oral bacteria with multiple doses (4-75 mg). Besides adverse events (Phase 1), outcome measures included whole-mouth plaque and gingival index scores and bleeding on probing (Phase 2a). KSL-W demonstrated safety in both phases, with no severe adverse events. The proof-of-concept analysis revealed a decrease in plaque and gingival inflammation, particularly at doses ≥ 20 mg. The 30 mg dose appeared to yield optimal effects without any adverse reactions in subjects. Results from this study indicate that KSL-W is safe for use in humans and provides initial evidence of its potential efficacy in reducing plaque and gingival inflammation. Further research is essential to determine optimal usage and ultimate safety, and to assess its potential in diverse populations. The trial is registered with the FDA (Trial Registration Number: NCT01877421). The clinical trials were registered in the clinicaltrials.gov database under the title "Safety and Tolerability of Antiplaque Chewing Gum in a Gingivitis Population" and the identifier number is NCT01877421. The URL for accessing the study in clinicaltrials.gov is https://clinicaltrials.gov/study/NCT01877421?intr=Antiplaque%20chewing&rank=1.

Transforming Stroke Recovery: The Bobath Concept in a Case Study of Middle Cerebral Artery Infarction

Stroke remains a major cause of long-term disability, necessitating effective rehabilitation strategies. This case study examines the rehabilitation of a 57-year-old male patient recovering from a middle cerebral artery (MCA) infarction, utilising the Model of Bobath Clinical Practice (MBCP). The patient underwent interventions based on the Bobath concept, focusing on selective activation of trunk muscles, core engagement, and pelvic alignment to enhance postural control. Assessments revealed significant improvements in both sitting and standing postures, with reductions in compensatory fixation strategies. The targeted therapeutic exercises facilitated better trunk control and lower limb weight-bearing, resulting in overall enhanced stability. The findings underscore the importance of individualised approaches in stroke rehabilitation aligned with Bobath principles. While the outcomes are promising, further research is needed to confirm the effectiveness of the MBCP model across varied patient populations. This study highlights the potential of the Bobath Concept in improving functional recovery and quality of life for stroke survivors.

Selective Activation of Peptide‐Thioester Precursors for Templated Native Chemical Ligations

AbstractChemical protein synthesis enables access to proteins that would otherwise be difficult or impossible to obtain with traditional means such as recombinant expression. Chemoselective ligations provide the ability to join peptide segments prepared by solid‐phase peptide synthesis. While native chemical ligation (NCL) is widely used, it is limited by the need for C‐terminal thioesters with suitable reaction kinetics, properly placed native Cys or thiolated derivatives, and peptide segment solubility at low mM concentrations. Moreover, repetitive purifications to isolate ligated products are often yield‐sapping, hampering efficiency and progress. In this work, we demonstrate the use of Controlled Activation of Peptides for Templated NCL (CAPTN). This traceless multi‐segment templated NCL approach permits the one‐pot synthesis of proteins by harnessing selective thioester activation and orthogonal conjugation chemistries to favor formation of the full‐length ligated product while minimizing side reactions. Importantly, CAPTN provides kinetic enhancements allowing ligations at sterically hindered junctions and low peptide concentrations. Additionally, this one‐pot approach removes the need for intermediate purification. We report the synthesis of two E. coli ribosomal subunits S16 and S17 enabled by the chemical tools described herein. We anticipate that CAPTN will expedite the synthesis of valuable proteins and expand on templated approaches for chemical protein synthesis.

Controllable Regulation of CO2 Adsorption Behavior via Precise Charge Donation Modulation for Highly Selective CO2 Electroreduction to Formic Acid.

The synthesis of value-added products via CO2 electroreduction (CO2ER) is of great significance, but the development of efficient and versatile strategies for the controllable selectivity tuning is extremely challenging. Herein, the tuning of CO2ER selectivity through the modulation of CO2 adsorption behavior is proposed. Using the constructed zeolitic MOF (SNNU-339), CO2 adsorption behavior is controllably changed from *CO2 to CO2* via the precise ligand-to-metal charge donation (LTMCD) regulation. It is confirmed that the high electronegativity of the coordinate ligand directly restricts the LTMCD, reduces the charge density on the metal sites, lowers the Gibbs free energy for CO2* adsorption, and leads to the transformation of CO2 adsorption mode from *CO2 to CO2*. Owing to the modulated CO2 adsorption behavior and regulated kinetics, SNNU-339 exhibits superior HCOOH selectivity (≈330% promotion, 85.6% Faradaic efficiency) and high CO2ER activity. The wide applicability of the proposed approach sheds light on the efficient CO2ER. This study provides a competitive strategy for rational catalyst design and underscores the significance of adsorption behavior tuning in electrocatalysis.

Effect of charge state on alkaline OER activity in FeN4−Gr catalyst supported on Ni (111) substrate

Abstract The catalysts of transition metal single−atom embedded in N−doped graphene (TMN4−Gr) have attracted significant attention due to the high utilization of transition metal atoms, remarkable selectivity and tunable catalytic activity. In this study, we have employed first−principles study to investigate alkaline OER activity of FeN4−Gr system supported on a Ni (111) substrate (FeN4−Gr/Ni). The results show that the Ni substrate can significantly enhance the OER activity of FeN4−Gr catalyst. The overpotential of FeN4−Gr/Ni catalyst is 0.63 V, much lower than 0.79 V of the FeN4−Gr, which is closely related to the strong interaction from the Ni substrate. By subtracting electrons from the FeN4−Gr/Ni catalyst, a positive charge environment can be created. It is found that, between the FeN4−Gr and the Ni substrate, a significant electron transfer phenomenon is observed, and the amount can be regulated by the charge state. Besides, the charge state can obviously tune the adsorption strength of *OOH intermediate through the interaction of Ni substrate, further optimizing the OER activity thermodynamically favorable. As the charge state increases to +1.55, the overpotential decreases to 0.23 V. By analyzing the integrated crystal orbital Hamilton populations, the chemical bond strength of Fe−O is discussed. Our results reveal that the Ni substrate can significantly enhance the OER activity of the FeN4−Gr catalyst, and the charge state can also tune the overpotential, offering valuable insights for the design of high−efficiency single−atom catalysts utilizing metal substrate.

Modular Plasmonic Nanopore for Opto‐Thermal Gating

AbstractSolid‐state nanopore gating inspired by biological ion channels is gaining increasing traction due to a large range of applications in biosensing and drug delivery. Integration of stimuli‐responsive molecules such as poly(N‐isopropylacrylamide) (PNIPAM) inside nanopores can enable temperature‐dependent gating, which so far has only been demonstrated using external heaters. In this work, plasmonic resonators are combined inside the nanopore architecture with PNIPAM to enable optical gating of individual or multiple nanopores with micrometer resolution and a switching speed of a few milliseconds by thermo‐plasmonics effects. A temperature change of 40 kelvin per millisecond is achieved and demonstrates the efficacy of this method using nanopore ionic conductivity measurements that enable selective activation of individual nanopores in an array. Moreover, the selective gating of specific nanopores in an array can set distinct ionic conductance levels: low, medium, and high (i.e., “0,” “1,” and “2”), which can be exploited for logical gating with optical signal control. Such selective optical gating in nanopore arrays marks a breakthrough in nanofluidics, as it paves the way toward smart devices that offer multifunctional applications including biosensing, targeted drug delivery, and fluidic mixing.

Optogenetic stimulation recruits cortical neurons in a morphology-dependent manner.

Single-photon optogenetics enables precise, cell-type-specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bares promise for Brain-Machine Interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cat of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers.Significance Statement Sensory features, such as the position or orientation of a visual stimulus, are mapped onto the surface of cortex as functional domains. Their selective activation, that may enable eliciting complex percepts, is intensively pursued for basic science and clinical applications. However, delivery of light into one functional domain in optogenetically transfected cortex results in complex, widespread neuronal activity, spreading beyond the targeted domain. Our computational study reveals that neuron morphology contributes to this diffuse response in a cortical-layer and intensity-dependent manner. We show that enhancing the stimulator optics is more effective than soma-targeting of the opsin in increasing spatial precision of stimulation. Our simulations provide insights for designing optogenetic stimulation protocols and hardware to achieve selective activation of functional domains.

Mechanistic Perspective on Oxygen Activation Chemistry by Flavoenzymes.

Flavin-dependent enzymes catalyze a panoply of chemical transformations essential for living organisms. Through oxygen activation, flavoenzymes could generate diverse flavin-oxygen species that mediate numerous redox and non-redox transformations. In this review, we highlight the extensive oxygen activation chemistry at two sites of the flavin cofactor: C4a and N5 sites. Oxygen activation at the C4a site generates flavin-C4aOO(H) species for various monooxygenation reactions, while activation at the N5 site produces negatively charged flavin-N5OOH species, which act as highly reactive nucleophiles or bases. The selective oxygen activation at either the C4a or N5 site depends on the nature of substrates and is controlled by the active site architecture. These insights have expanded our understanding of oxygen activation chemistry in flavoenzymes and will serve as a foundation for future efforts in enzyme engineering and redesign.

Single-Dose Drug Development Candidate for Schistosomiasis.

Aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. However, as exemplified by Ro 13-3978, this compound series produced antiandrogenic side effects on the host, a not unexpected outcome given their structural similarity to the antiandrogenic drug nilutamide. The two key advances in our optimization of Ro 13-3978 were swapping the aryl trifluoromethyl substituent with a difluoroethyl to abolish antiandrogenic effects and replacing the hydrogen atoms of the gem-dimethyl substructure with deuterium atoms to increase metabolic stability. Combining these two structural changes led to the discovery of single-dose drug candidate AR102, a compound with potent, selective, and broad-spectrum activity against schistosomes, a long pharmacokinetic half-life in preclinical species, and an acceptable safety profile.

Semisynthetic Ecdysteroid Cinnamate Esters and tert-Butyl Oxime Ether Derivatives with Trypanocidal Activity.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects the lives of millions of indigenous people in Latin America. As medications to treat Chagas disease are limited to the application of benznidazole and nifurtimox, which are not ideal treatments for the chronic stage of the disease, the search for new antichagasic drug candidates is an important need. Ecdysone has previously been shown to interfere with the life cycle of T. cruzi. Here, we report the biological profiling and subsequent semisynthetic structure optimization of 47 ecdysteroids against T. cruzi with the aim of identifying selective trypanocidal ecdysteroids. Two moderately trypanocidal pharmacophores were identified: ecdysteroids containing a 6-tert-butyl oxime ether and a cinnamic ester moiety. These functional groups were combined into the structures of four new semisynthetic ecdysteroids (44-47), among which 44 exerted potent and selective trypanocidal activity (IC50 < 2 μM). Cellular infection assays showed that ecdysteroid 44 potently and efficiently inhibited amastigote replication as determined by trypomastigote release after cellular infection with an IC50 of 2.7 ± 0.1 μM. The compound was similarly potent to benznidazole (IC50 = 3.8 ± 0.7 μM) and more than 5-fold more cytotoxic toward T. cruzi over RAW264.7 host macrophages. Overall, the ecdysteroid cinnamate ester 44 is a novel trypanocidal lead structure that needs to be further characterized in follow-up studies.