Phenoxyl Group Research Articles

Neutral and Anion Species of Quinoidal Thienothiophene Diketopyrrolopyrroles Display a Common Aggregation Mode.

A comprehensive investigation of two new molecular triads incorporating the diketopyrrolopyrrole unit into a quinoidized thienothiophene skeleton, which is further end-capped with dicyanomethylene (DPP-TT-CN) or phenoxyl groups (DPP-TT-PhO), has been carried out. A combination of UV-Vis-NIR and infrared spectroelectrochemical techniques and cryogenic UV-Vis-NIR absorption spectroscopy supported by theoretical calculations has been used. The main result is the formation of similar H-aggregates in the dimerization process of the neutral molecules and of the charged anionic species. The experimental absorption spectra of the aggregated species are accurately reproduced by quantum chemical calculations using the Spano's model, including excitonic coupling for the dimeric forms and full vibronic resolution of the absorption bands. The strong excitonic coupling taking place is key to understand the electronic structure of the dimeric species and has been instrumental to disentangle the type of H-aggregation. This study is of relevance to get a better understanding of the molecular aggregation of organic π-conjugated chromophores and is useful as a guideline for the refinement of the engineering of molecular materials for which supramolecular design is required.

Flavonoids as Protein Disulfide Isomerase Inhibitors: Key Molecular and Structural Features for the Interaction.

Quercetin-3-rutinoside (rutin) is a bioflavonoid that is common in foods. The finding that quercetin-3-rutinoside inhibits protein disulfide isomerase (PDI) and potently blocks thrombosis in vivo has enabled the evaluation of PDI inhibition in multiple animal models of thrombus formation and has prompted clinical studies of PDI inhibition in thrombosis. Nonetheless, how quercetin-3-rutinoside blocks PDI activity remains an unanswered question. Combining NMR spectroscopy, site-directed mutagenesis, and biological assays, we identified H256 as the key residue for PDI interacting with quercetin-3-rutinoside. Quercetin-3-rutinoside inhibited the activity of PDI (WT) but not PDI (H256A). Molecular dynamic simulations indicated that the flavonoid skeleton, but not the rutinoside conjugate, is embedded in the major binding pocket on the b' domain. Among several quercetin-3-rutinoside analogues tested, only compounds with a phenoxyl group at position 7 showed direct binding to PDI, further supporting our molecular model. Studies using purified coagulation factors showed that quercetin-3-rutinoside inhibited the augmenting effects of PDI (WT), but not PDI (H256A), on tissue factor (TF) activity. Quercetin-3-rutinoside also inhibited chemotherapy-induced TF activity enhancement on endothelial cells. Together, our studies show that residue H256 in PDI and the phenoxyl group at position 7 in quercetin-3-rutinoside are essential for inhibition of PDI by quercetin-3-rutinoside. These results provide new insight into the molecular mechanism by which flavonoids block PDI activity.

SET and HAT/PCET acid-mediated oxidation processes in helical shaped fused bis-phenothiazines.

Helical shaped fused bis‐phenothiazines 1–9 have been prepared and their red‐ox behaviour quantitatively studied. Helicene radical cations (Hel.+) can be obtained either by UV‐irradiation in the presence of PhCl or by chemical oxidation. The latter process is extremely sensitive to the presence of acids in the medium with molecular oxygen becoming a good single electron transfer (SET) oxidant. The reaction of hydroxy substituted helicenes 5–9 with peroxyl radicals (ROO.) occurs with a ‘classical’ HAT process giving HelO. radicals with kinetics depending upon the substitution pattern of the aromatic rings. In the presence of acetic acid, a fast medium‐promoted proton‐coupled electron transfer (PCET) process takes place with formation of HelO. radicals possibly also via a helicene radical cation intermediate. Remarkably, also helicenes 1–4, lacking phenoxyl groups, in the presence of acetic acid react with peroxyl radicals through a medium‐promoted PCET mechanism with formation of the radical cations Hel.+. Along with the synthesis, EPR studies of radicals and radical cations, BDE of Hel‐OH group (BDEOH), and kinetic constants (kinh ) of the reactions with ROO. species of helicenes 1–9 have been measured and calculated to afford a complete rationalization of the redox behaviour of these appealing chiral compounds.

Noncovalent interactions in catechol/ammonium-rich adhesive motifs: Reassessing the role of cation-π complexes?

Cation-π interactions between ammonium and catechol groups provide a commonly held paradigm in the complex interplay of noncovalent forces that govern both biological phenomena, such as underwater adhesion in mussel byssus and other marine organisms, and aggregation processes in self-assembly of catecholamine-derived polymers. However, closer consideration of the peculiar properties of the catechol functionality, that features two adjacent phenoxyl groups endowed with chelating properties, would suggest operation of alternate interaction geometries besides typical cation-π. Following previous studies on various alkali metal cations, we report herein compelling computational evidence in favor of a so far overlooked σ-type interaction between the ammonium cation and the catechol system, as the most important contributor to binding, far exceeding the cation-π component. The present findings would hence prompt an experimental and theoretical reassessment of the actual importance of cation-π against σ-type interaction between ammonium and catechol groups in underwater adhesive patterns. In this framework, the catechol-ammonium interaction energy potential surfaces herein reported may provide an improved reference to approach more realistic natural and synthetic adhesion models encompassing other participating molecules/ions and the role of the solvent.

Effect of urea on chlorinated aromatics formation mediated by copper and iron species in combustion flue gas

Urea ((NH2)2CO) is widely applied to the reduction of NOX in modern full-scale solid waste incineration systems, but there is a lack of knowledge about how urea affects the formation and emission of Cl-aromatics. In this study, we investigated the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated polychlorinated naphthalenes (PCNs) via electrophilic chlorination and precursor pathway mediated by model fly ashes containing Cu and Fe species with or without urea addition. The results indicated that the addition of urea promoted the direct chlorination of parent aromatics over Cu (Ⅱ) chlorides and the coupling reaction of chlorophenols over Fe species, while suppressed the catalytic chlorination of parent aromatics over Fe (Ⅲ) chlorides and the coupling reaction of chlorophenols over Cu species. The diverse effects should be mainly attributed to the formation of complex salts containing NH3 and NH4+. The formation of complex salts of Fe chlorides and NH4Cl could hinder the oxidization of Fe chlorides, and thus maintain the high activity of Fe species for catalyzing the coupling reaction of chlorophenols. The formation of complex salts of Cu (Ⅱ) chloride and NH3 could prevent the chemical sorption of phenoxyl groups, and thus suppress the coupling reaction of chlorophenols. NH3 released from the thermal decomposition of urea could not only react with Cl2 to suppress the catalytic chlorination of aromatics, but also neutralize HCl to accelerate the direct chlorination of aromatics. In general, urea should act as inhibitor for suppressing the formation of Cl-aromatics in solid waste incineration systems.

Radiation-Induced Processes in Diazoquinone–Novolac Resist Films under Irradiation with 60Co γ-Rays

The processes occurring under the irradiation of FP9120 diazoquinone–novolac resist films on silicon with 60Co γ-rays have been studied by attenuated total reflectance (ATR) FTIR spectroscopy. It has been found that a significant modification of the ATR spectra of the photoresist films was noticeable only at absorbed doses above 200 kGy, and it occurred due to the radiation-induced transformations of methyl, methylene, hydroxymethyl, and phenoxyl groups of phenol–formaldehyde resin and o-naphthoquinone diazide (a photosensitive component). At the same time, the ATR spectra exhibited no signs of the destruction of aromatic fragments in the resist at doses to 300 kGy. In the region of the stretching vibrations of C=O bonds, a decrease in the maximum intensity of a band at ~1700 cm–1 was observed upon irradiation with its simultaneous broadening and shift to the high-energy region by ~30 cm–1 due to a change in the nearest environment of the C=O group. An increase in the absorption band intensity at 1650 cm–1 indicated the accumulation of formaldehyde upon the γ-irradiation of the resist as a result of the fragmentation of hydroxymethyl residues in the phenol–formaldehyde resin.

One Electron Multiple Proton Transfer in Model Organic Donor-Acceptor Systems: Implications for High Frequency EPR.

EPR spectroscopy is an important spectroscopic method for identification and characterization of radical species involved in many biological reactions. The tyrosyl radical is one of the most studied amino acid radical intermediates in biology. Often in conjunction with histidine residues, it is involved in many fundamental biological electron and proton transfer processes, such as in the water oxidation in photosystem II. As biological processes are typically extremely complicated and hard to control, molecular bio-mimetic model complexes are often used to clarify the mechanisms of the biological reactions. Here we present theoretical calculations to investigate the sensitivity of magnetic resonance parameters to proton-coupled electron transfer events, as well as conformational substates of the molecular constructs which mimic the tyrosine-histidine (Tyr-His) pairs found in a large variety of proteins. Upon oxidation of the phenol, the Tyr analogue, these complexes can perform not only one-electron one-proton transfer (EPT), but also one-electron two-proton transfers (E2PT). It is shown that in aprotic environment the gX-components of the electronic g-tensor are extremely sensitive to the first proton transfer from the phenoxyl oxygen to the imidazole nitrogen (EPT product), leading to a significant increase of the gX-value of up to 0.003, but are not sensitive to the second proton transfer (E2PT product). In the latter case the change of the gX-value is much smaller (ca. 0.0001), which is too small to be distinguished even by high frequency EPR. The 14N hyperfine values are also too similar to allow differentiation between the different protonation states in EPT and E2PT. The magnetic resonance parameters were also calculated as a function of the rotation angles around single bonds. It was demonstrated that rotation of the phenoxyl group results in large positive changes (>0.001) in the gX-values. Analysis of the data reveals that the main source of these changes is related to the strength of the H-bond between phenoxyl oxygen and the proton(s) on N1 and N2 positions of the imidazole.

Thermostable α-Diimine Nickel Complexes with Substituents on Acenaphthequinone-backbone for Ethylene Polymerization

In order to promote the thermostability of α-diimine nickel complex by ligand backbone structure, a series of α-diimine nickel complexes with substituents on acenaphthequinone backbone were synthesized and used as catalysts for ethylene polymerization. When the hydroxyethyl phenoxyl group was introduced to the acenaphthequinone-backbone, the thermal stability and activity of the catalyst could be significantly improved. The catalytic activity of complex C2 [5-(4-(2-hydroxyethyl)phenoxyl)-N,N-bis(2,6-diisopropyl)acenaphthylene-1,2-diimine]nickel(II) dibromide with isopropyl substituents on N-aryl reached 8.2 × 106 g/(molNi·h) at 70 °C and 2 MPa. The activity of [5-(4-(2-hydroxyethyl)phenoxyl)-N,N-bis(2,6-dibenzhydryl-4-menthylphenyl)acenaphthylene-1,2-diimine]nickel(II) dibromide (C3) still maintained at 6.7 × 105 g/(molNi·h) at 120 °C. Compared with C3 containing bulky dibenzhydryl substituents, the activity of C2 was sensitive to the change of the polymerization pressure. However, the polyethylenes obtained from complex C3 had lower branching density. Meanwhile, the molecular weight could reach 971 kg/mol, which is almost 5 times as much as that of the polyethylene obtained from complex C2.

Novel azaphthalocyanines with efficient anti-corrosion capability: Effect of halogens and heavy metals

A series of azaphthalocyanines (AzaPcs) substituted with peripheral 2,6-dihalogenated (Cl, Br or I) phenoxyl groups containing different central ions [2H+, Zn (II), Mg (II) or In (III)] were synthesized and their structural characterization were confirmed. Non-aggregation behavior exhibited by all the prepared complexes was perfectly achieved as confirmed by single crystal analyses due to the bulkiness of their peripheral substituents. Based on physicochemical analyses including fluorescence and singlet oxygen quantum yields, heavy metal effects were determined, and consequently, the highest singlet oxygen was recorded by the indium complex bearing iodine atoms (AzaPc12). The electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP) results revealed that the investigated azaphthalocyanine molecules pronouncedly retarded the mild steel corrosion in the acidic media by adsorbing at the metal/electrolyte interface. Theoretical DFT and molecular dynamic simulation studies supported the experimental results with the best inhibition efficiency achieved with AzaPc12. Surface morphology of mild-steel was examined by AFM and SEM techniques. The results proved the strong adsorption of AzaPc12 on the steel surface, forming a protective film which consistent with the electrochemical and theoretical results. The findings of this research obviously show a simple approach to the manufacture of phthalocyanine-derivatives that can find significant industrial application in metal corrosion suppression.

Laccase Induced Lignin Radical Formation Kinetics Evaluated by Electron Paramagnetic Resonance Spectroscopy

Laccases (EC 1.10.3.2) catalyze oxidation of phenoxyl groups in lignin during reduction of O2, and the first product is a lignin radical. The determination of laccase kinetics on lignin requires ca...

Assembly of Mn(III) Schiff Base Complexes with Heptacyanorhenate (IV)

A pioneering research on a self-assembly of the magneto-anisotropic module [Re(CN)7]3− with the Mn(III) complexes involving Salen type (N,N′-ethylenebis(salicylideneiminate)) Schiff base (SB) ligands was performed using the known [Mn(3MeOSalen)(H2O)2]2(ClO4)2·H2O (1) and the firstly synthesized [Mn2(5MeSalen)2OAc]PF6 (2). In the case of 1, a slow diffusion of the component solutions led to the ionic compound Ph4P[Mn(3MeOSalen)(H2O)2]2[Re(CN)7]·6H2O (3). The direct mixing of the same solutions has resulted in the microcrystalline nearly insoluble solid [Mn(3MeOSalen)(H2O))4Re(CN)7]ClO4·1.5MeCN·6.5H2O, which is likely to comprise the pentanuclear clusters [(MnIII(SB)(H2O))4Re(CN)7]+. The use of 2 resulted in a 2D-network assembly of octanuclear clusters, [{(Mn(5MeSalen))6(H2O)2Re(CN)7}2Re(CN)7]Cl2(PF6)·H2O (4), incorporating one Re-center in a pentagonal bipyramid coordination environment, while another has strongly distorted capped trigonal prism as a coordination polyhedron. The latter was observed for the first time for Re(IV) complexes. A synthetic challenge to obtain the 0D assemblies with Re:Mn ≥ 3 has yielded a hexanuclear complex [Mn(5MeSalen)H2O(i-PrOH)][(Mn(5MeSalen))5H2O(i-PrOH)2Re(CN)7](PF6)2(OAc)·2i-PrOH (5) being 1D chain via a bridging phenoxyl group. Owing to a low solubility of the final product, an addition of a bulk anion Ph4B− to the MeCN/MeOH solution of [Re(CN)7]3−and 1 in ratio 1:6 resulted in rhenium-free matter [Mn(3MeOSalen)(H2O)2][Mn(3MeOSalen)(H2O)MeCN](Ph4B)2·5MeCN (6).

Third‐Order Nonlinear Optical Properties of One‐Dimensional Quinoidal Oligothiophene Derivatives Involving Phenoxyl Groups

The diradical characters (y) and third‐order nonlinear optical (NLO) properties of open‐shell quinoidal oligothiophene derivatives with phenoxyl groups, and the corresponding reduced (hydrogenated)‐state oligomers, are investigated by using the broken‐symmetry density functional theory method. The oxidized (dehydrogenated) states are predicted to have an open‐shell singlet ground state and their y values increase with the number of units. Static second hyperpolarizabilities (γ) of the open‐shell oligomers with intermediate y are shown to be enhanced significantly compared with those of the closed‐shell analogues. Furthermore, owing to the effective diradical distances, the γ values of open‐shell oligomers are found to exceed that of s‐indaceno[1,2,3‐cd;5,6,7‐c′d′]diphenalene, which is known as an organic molecule with the largest two‐photon absorption cross‐section in this size of the pure hydrocarbons. This feature extends the range of efficient open‐shell third‐order NLO materials to a novel class of one‐dimensional conjugated oligomers with redox‐based high tunability of third‐order NLO properties.

Cationic sulfonium functionalization renders Znsalens with high fluorescence, good water solubility and tunable cell-permeability.

In this study, we report for the first time that incorporation of cationic sulfonium to the Znsalens skeleton achieves water soluble fluorescent metal complex probes for living cell imaging. To circumvent Znsalen aggregation arising from intermolecular ZnO interactions (found between Zn and the phenoxyl group of another Znsalen molecule), we synthesized a series of sulfonium Znsalens based on alkylation of the 3-thioether or 3,5-dithioether moieties of salicylaldehydes. Such functionalization not only provides positive charge(s) to enhance electrostatic repulsion, but also increases steric hindrance, which renders the Znsalen complex water soluble as a monomeric species in aqueous media as revealed by diffusion ordered NMR spectroscopy (DOSY). More interestingly, these sulfonium Znsalens display "switched on" fluorescence when compared to thioether analogues, which was attributed to the electron-withdrawing sulfonium moiety that perturbs the photoinduced electron transfer (PET) process as suggested by computational calculations based on time-dependent density functional theory (TD-DFT). Most interestingly, live cell imaging experiments showed that modulation of the sulfonium moieties, such as the number or alkyl substituents, significantly tunes the cell-permeability of the fluorescent Znsalens. Thus, this study has demonstrated the importance of sulfonium functionalization on dissociating the intermolecular metal-ligand interactions and thus, modulating water solubility, photophysical properties and even cell-permeability of the fluorophores, which provides a new approach to the design of functional metal complexes for biological studies.

Design of organic dyes for dye-sensitized solar cells: Extending π-conjugation backbone via ‘Click’ reaction to improve photovoltaic performances

The organic dyes have been synthesized via a ‘Click’ reaction and employed in dye-sensitized solar cells, in which an electron-deficient 1,2,3-triazole unit is introduced to connect the thienyl group and the phenoxyl group as π-linkers. Compared with the non-thiophene containing reference dye, these new dyes show stronger intramolecular charge transfer and higher molar extinction coefficient with incremental increase of thienyl groups. Thus, the short-circuit current of solar cells based on them is greatly increased. Moreover, the existence of 1,2,3-triazole unit is favorable for the charge separation that can retard the charge recombination and improve the open circuit voltage. Consequently, the solar cell based on the dithienyl containing dye presents the best performance with a Jsc of 10.00 mA cm−2, a Voc of 0.68 V and a FF of 0.71, corresponding to an overall conversion efficiency of 4.81% among them.

Synthesis of xanthohumol analogues and discovery of potent thioredoxin reductase inhibitor as potential anticancer agent.

The selenoprotein thioredoxin reductases (TrxRs) are attractive targets for anticancer drugs development. Xanthohumol (Xn), a naturally occurring polyphenol chalcone from hops, has received increasing attention because of its multiple pharmacological activities. We synthesized Xn and its 43 analogues and discovered that compound 13n displayed the highest cytotoxicity toward HeLa cells (IC50 = 1.4 μM). Structure-activity relationship study indicates that the prenyl group is not necessary for cytotoxicity, and introducing electron-withdrawing group, especially on the meta-position, is favored. In addition, methylation of the phenoxyl groups generally improves the potency. Mechanistic study revealed that 13n selectively inhibits TrxR and induces reactive oxygen species and apoptosis in HeLa cells. Cells overexpressing TrxR are resistant to 13n insult, while knockdown of TrxR sensitizes cells to 13n treatment, highlighting the physiological significance of targeting TrxR by 13n. The clarification of the structural determinants for the potency would guide the design of novel potent molecules for future development.

Activation of Nrf2 target enzymes conferring protection against oxidative stress in PC12 cells by ginger principal constituent 6-shogaol.

Natural compounds containing phenoxyl groups and/or Michael acceptor units appear to possess antioxidant and cytoprotective properties. The ginger principal constituent 6-shogaol (6-S) represents one of such compounds. In this study, we reported that 6-S efficiently scavenges various free radicals in vitro, and displays remarkable cytoprotection against oxidative stress-induced cell damage in the neuron-like rat pheochromocytoma cell line, PC12 cells. Pretreatment of PC12 cells with 6-S significantly upregulates a series of phase II antioxidant molecules, such as glutathione, heme oxygenase 1, NAD(P)H: quinone oxidoreductase 1, thioredoxin reductase 1, and thioredoxin 1. A mechanistic study revealed that 6-S enhanced the translocation of Nrf2 from the cytosol to the nucleus and knockdown of Nrf2 abolished such protection, indicating that this cytoprotection is mediated by the activation of the transcription factor Nrf2. Another ginger constituent 6-gingerol (6-G), having a similar structure of 6-S but lacking the alpha,beta-unsaturated ketone structure (Michael acceptor moiety), failed to shelter PC12 cells from oxidative stress. Our results demonstrate that 6-S is a novel small molecule activator of Nrf2 in PC12 cells, and suggest that 6-S might be a potential candidate for the prevention of oxidative stress-mediated neurodegenerative disorders.

Synthesis and Herbicidal Activity of 2-Cyano-3-(2-substituted phenyoxypyridin-5-yl) Amino Acrylates Containing Substituted Phenoxyl Group

以氰基吡啶氨基丙烯酸酯类化合物为母体，合成了两个系列的含取代苯氧基的2-氰基-3-（2-取代吡啶-5-甚）氨蛙丙烯酸酯化合物，即光系统Ⅱ（PSⅡ）电子传递抑制剂，以考察不同苯氧基在两个关键位点对其生物活件的影响．牛洲绝果表明：这两个系列化合物均显示出一定的除草活性，其中几种化合物在处理剂量为1．5kg／ha时，对油菜等阔叶杂草的茎叶处理后的鲜重抑制率达90％以上．从构效关系上，可以初步推测不同苯氧取代基位于氨基吡啶基对位上对除草活性的贡献与其母体氨基吡啶基化合物大致相当，且选择性更好；而在酯基部分对除草活性的贡献不明湿．

Synthesis of multi-imidazolium salt ligands containing calixarene fragments and their N-heterocyclic carbene Ag(I) macrocyclic complexes

The unsymmetric bis-imidazolium salts ligands 4a and b were prepared by stepwise reactions of 2,6-bis(bromomethylene)-4-(t-butyl)anisole (1) with two different N-substituted imidazoles. Reaction of the bis-imidazolium ligands with Ag2O in acetonitrile gave the dinuclear bis(N-heterocyclic carbene) complexes 5a and b. The molecular structure of complex 5a was determined by single-crystal X-ray diffraction analysis. In complex 5a and b, the two Ccarbene–Ag–Ccarbene axes are in a crossed conformation, two O atoms from phenoxyl groups weakly coordinate to different Ag ions and the two p-t-butylphenoxyl groups adopted a staggered conformation. To regulate the molecular shape of the N-heterocyclic carbene Ag(I) macrocyclic complexes, two tetradentate imidazolium ligands (9a and b) were prepared. The bimetallic NHC–Ag(I) complexes 10a and b were obtained by the reaction of 9a and b and Ag2O in acetonitrile. Constrained by the chain (the dioxoethylene or dioxomethylenebenzene chain in 10a or 10b, respectively) at the O-position of the phenoxyl group, the two p-methylphenoxyl groups in complexes 10a and b might be predicted to have a cone conformation. The ligands and the corresponding NHC metal complexes have been characterized by elemental analysis, 1H NMR and 13C NMR, HRMS spectra, as well as TGA and DTA spectra being determined for complexes 10a and b. The TGA curves show that these NHC–Ag complexes have good thermal stability.

Chiral MnIII(Salen) supported on tunable phenoxyl group modified zirconium poly (styrene-phenylvinylphosphonate)-phosphate as an efficient catalyst for epoxidation of unfunctionalized olefins

We have developed a series of chiral MnIII(Salen) (chiral Jacobsen's catalyst) catalysts that were axially supported onto zirconium poly(styrene-phenylvinylphosphonate)-phosphate through tunable phenoxyl linkers of varying steric hindrance, and evaluated their performance as catalysts (Cat1–Cat3) for the epoxidation of unfunctionalized olefins using m-chloroperbenzoic acid as an oxidant. The corresponding non-supported analogues (Cat4–Cat6) were also prepared and tested under similar conditions. The results demonstrated that the incorporation of substituents at the ortho-positions of the tunable phenoxyl linkers had a critical effect on the catalytic activity. Furthermore, the enantioselectivity increased as the steric hindrance imposed by the linker increased, although this also led to a decrease in the conversions under the same reaction conditions, especially for heterogeneous epoxidation. The heterogeneous system also displayed high ee values and conversions in the absence of the axial additive N-methylmorpholine N-oxide, which is commonly required to improve the catalytic activity of epoxidation reactions, especially for the epoxidation of α-methylstyrene. The reusability of the catalyst was also evaluated over 11 catalytic cycles, with no significant reduction observed in the catalytic activity or enantioselectivity after five runs.

Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death

Chagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year. T. cruzi is susceptible to thiosemicarbazones, making this class of compounds appealing for drug development. Previously, the homologation of aryl thiosemicarbazones resulted in an increase in anti-T. cruzi activity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new aryl thiosemicarbazones (9a–x), designed as more conformationally restricted compounds. By varying substituents attached to the phenyl ring, substituents were observed to retain, enhance or greatly increase the anti-T. cruzi activity, in comparison to the nonsubstituted derivative. In most cases, hydrophobic and bulky substituents, such as bromo, biphenyl and phenoxyl groups, greatly increased antiparasitic activity. Specifically, thiosemicarbazones were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting mouse splenocytes viability. The most potent anti-T. cruzi thiosemicarbazones were evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these thiosemicarbazones induce apoptosis. In conclusion, the structural design executed within the series of aryl thiosemicarbazones (9a–x) led to the identification of new potent anti-T. cruzi agents, such as compounds (9h) and (9r), which greatly inhibited epimastigote proliferation, and demonstrated a toxicity for trypomastigotes, but not for splenocytes. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process.