Toxicity and effects on anuran tadpole metamorphosis of the anthranilic diamide insecticides chlorantraniliprole and cyantraniliprole.

The present study examined the acute and chronic toxicity attributed to commercial formulations of the anthranilic diamide insecticides chlorantraniliprole (CHLO) and cyantraniliprole (CYAN) on the neotropical amphibian species Rhinella arenarum, Rhinella fernandezae and Scinax granulatus. The median lethal concentrations obtained after 96 hr exposure (96 hr-LC50) were generally greater than 100 mg/L, except for stage 25 S. Granulatus, which were the most sensitive animals tested with a 96 hr-LC50 value of 46.78 mg/L. In subchronic exposures of R. arenarum, the 21day-LC50 were 151.4 mg/L for CHLO and >160 mg/L for CYAN, the weight gain of the tadpoles during this period not being markedly affected in both cases. Finally, when tadpoles of R. arenarum were exposed to CHLO throughout the metamorphic process, an inverted U-shaped non-monotonic dose-response relationship was observed between exposure concentrations and both % of individuals transiting between stage 39 and 42 and the time required to accomplish this. Data obtained raise the hypothesis of an effect of CHLO on the hypothalamic-pituitary-thyroid (HPT) axis, either directly or through an interaction with the stress-hormone system, as metamorphic progression from stage 39 to S42 occurs under the strict control of thyroid hormones. These observations are important as the anthranilic diamide insecticides are not currently known as endocrine disruptors. Further investigations are needed to clarify the pathways leading to these effects and examine whether environmentally-relevant aquatic concentrations of anthranilic diamides might be impacting amphibian populations in the wild.

Ecotoxicity of neonicotinoids and diamides on population growth performance of Zygogramma bicolorata (Coleoptera: Chrysomelidae).

Relative ecotoxicity of approved neonicotinoids (i.e. imidacloprid, clothianidin, acetamiprid, thiacloprid, thiamethoxam and dinotefuran) and diamides (i.e. chlorantraniliprole, cyantraniliprole and flubendiamide) was examined on population growth parameters of Zygogramma bicolorata Pallister on parthenium under laboratory conditions at 27 ± 1 °C, 65 ± 5% relative humidity and 10 L : 14D photoperiod. The dose of all tested insecticides in the bioassay procedure was within a minimum range of their recommended field rate. In acute toxicity trial, imidacloprid caused highest rate of mortality in treated adults of Z. bicolorata, however, it was lowest in flubendiamide treatment followed by cyantraniliprole and chlorantraniliprole. Further, based on toxicity coefficient (E) value in acute toxicity trial, all were classified as harmful (H) and diamides were classified as moderately harmful (MH) as per IOBC classification. Moreover, chronic toxicity trials were carried out through life table response experiments (LTREs) in the F1 progeny of acute toxicity experienced group. Prolonged development with the highest mortality was evident in as compared to diamides. Furthermore, population growth parameters i.e. potential fecundity (Pf), natality rate (mx), intrinsic rate of increase (rm), net reproductive rate (R0) and finite rate of increase (λ) was greatly reduced in Z. bicolorata treated with neonicotinoids as compared with diamides. However, mean generation time (Tc), corrected generation time (τ) and the doubling time (DT) was prolonged in neonicotinoids followed by diamides. Furthermore, proportion of females was greatly reduced (0.43-0.48 females) in neonicotinoids as comparison to diamides (0.53-0.55 females) and control (0.67 females). On the basis of ecotoxicity trials, the tested neonicotinoids were highly toxic to Z. bicolorata than diamides. Therefore, diamide insecticides could be used with Z. bicolorata, however, for validation experimentation need to be done under natural field conditions.

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space.

Two novel solid reagents-1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives-for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pKa , Log P, microsomal stability, and reactivity towards typical electrophiles). Similar to other organosulfur(VI) derivatives with S=N bonds, these compounds can be considered as promising bioisosteres of amides, ureas, or sulfonamides.

Synthesis, insecticidal evaluation and mode of action of novel anthranilic diamide derivatives containing sulfur moiety as potential ryanodine receptor activators.

Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In order to discover new anthranilic diamide insecticide as ryanodine receptors activators, a series of 11 novel anthranilic diamides derivatives (Ia-k) were synthesized and confirmed by melting point, 1H NMR, 13C NMR and elemental analyses. The preliminary bioactivity revealed that most title compounds showed moderate to remarkable activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Especially, compounds Ia and If, which exhibited 100% larvicidal activity against oriental armyworm at 1.0 mg L-1, and comparable to that of chlorantraniliprole (100% at 1 mg L-1). If displayed 60% insecticidal activity against diamondback moth at 0.01 mg L-1, better than chlorantraniliprole (45% at 0.01 mg L-1). The preliminary structure activity relationships were discussed. In addition, the calcium imaging experiment indicated that the insect ryanodine receptor is the potential target of If.

Chlorantraniliprole-mediated effects on survival, walking abilities, and respiration in the coffee berry borer, Hypothenemus hampei.

Hypothenemus hampei Ferrari (Coleoptera: Curculionidae) is the main pest of coffee crops, and effective methods for pest management are needed urgently. Bioassays were conducted to assess the effects of the insecticide chlorantraniliprole on H. hampei adults. Toxicity, survivorship, larval production, respiration rate, and behavioral responses to six concentrations of chlorantraniliprole were evaluated. Chlorantraniliprole was toxic to H. hampei (LD50 = 0.49 mg mL-1 and LD90 = 1.21 mg mL-1). Survivorship was 98% in adults not exposed to chlorantraniliprole, decreasing to 52% in insects exposed to LD50 and 2% in insects treated with LD90. H. hampei showed reduced mobility on insecticide-treated surfaces. The insecticide promoted a decrease in the respiration rate of H. hampei for up to 3 h after exposure, altering behavioral responses and locomotor activity. Chlorantraniliprole was shown to have lethal and sublethal effects on H. hampei and, thus, can be used rotationally in integrated pest management programs to control of this pest in coffee crops and retard of insect resistance.

CuI/Oxalic Diamide-Catalyzed Cross-Coupling of Thiols with Aryl Bromides and Chlorides.

We report a general copper-catalyzed cross-coupling of thiols with aryl halides by using N-aryl-N'-alkyl oxalic diamide (L3) or N,N'-dialkyl oxalic diamide (L5) as the ligand. Both aryl and alkyl thiols can be coupled with unactivated aryl bromides and chlorides to give the desired products in good yields. Furthermore, this system features a broad substrate scope and good tolerance of functional groups. Importantly, the oxalic diamides are stable and can be prepared easily from commercially available and cheap starting materials.

Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity.

The diamide insecticides act on the ryanodine receptor (RyR). The synthesis of various bicyclic anthranilic derivatives is reported. Their activity against the insect ryanodine receptor (RyR) and their insecticidal activity in the greenhouse is presented, as well as structure activity relationship considerations.

Effectiveness of Cyantraniliprole for Managing Bemisia tabaci (Hemiptera: Aleyrodidae) and Interfering with Transmission of Tomato Yellow Leaf Curl Virus on Tomato.

Cyantraniliprole is the second xylem-systemic active ingredient in the new anthranilic diamide class. Greenhouse (2006), growth chamber (2007), and field studies (2009-2010) were conducted to determine the efficacy of cyantraniliprole for managing Bemisia tabaci (Gennadius) biotype B and in interfering with transmission of tomato yellow leaf curl virus (TYLCV) by this whitefly. Cyantraniliprole applied as soil treatments (200 SC) or foliar sprays (100 OD) provided excellent adult whitefly control, TYLCV suppression, and reduced oviposition and nymph survival, comparable to current standards. The positive results observed in these greenhouse experiments with a high level of insect pressure (10× the field threshold of one adult per plant) and disease pressure (five adults per plant, with a high level of confidence that TYLCV virulent adults were used), indicate a great potential for cyantraniliprole to be used in a whitefly management program. Field evaluations of soil drench treatments confirmed the suppression of TYLCV transmission demonstrated in the greenhouse studies. Field studies in 2009 and 2010 showed that cyantraniliprole (200 SC) provided TYLCV suppression for 2 wk after a drench application, when using a susceptible (2009) or imidacloprid-tolerant (2010) whitefly population. Cyantraniliprole was demonstrated to be a promising tool for management of TYLCV in tomato production, which is very difficult and expensive, and which has limited options. The integration of cyantraniliprole into a resistance management program will help to ensure the continued sustainability of this and current insecticides used for the management of insect vectors, including whiteflies and the TYLCV they spreads.

Key role of the ryanodine receptor I4790K mutation in mediating diamide resistance in Plutella xylostella.

The diamondback moth Plutella xylostella, a global insect pest of cruciferous vegetables, has evolved resistance to many classes of insecticides including diamides. Three point mutations (I4790M, I4790K, and G4946E) in the ryanodine receptor of P. xylostella (PxRyR) have been identified to associate with varying levels of resistance. In this study, we generated a knockin strain (I4790K-KI) of P. xylostella, using CRISPR/Cas9 to introduce the I4790K mutation into PxRyR of the susceptible IPP-S strain. Compared to IPP-S, the edited I4790K-KI strain exhibited high levels of resistance to both anthranilic diamides (chlorantraniliprole 1857-fold, cyantraniliprole 1433-fold) and the phthalic acid diamide flubendiamide (>2272-fold). Resistance to chlorantraniliprole in the I4790K-KI strain was inherited in an autosomal and recessive mode, and genetically linked with the I4790K knockin mutation. Computational modeling suggests the I4790K mutation reduces the binding of diamides to PxRyR by disrupting key hydrogen bonding interactions within the binding cavity. The approximate frequencies of the 4790M, 4790K, and 4946E alleles were assessed in ten geographical field populations of P. xylostella collected in China in 2021. The levels of chlorantraniliprole resistance (2.3- to 1444-fold) in these populations were significantly correlated with the frequencies (0.017-0.917) of the 4790K allele, but not with either 4790M (0-0.183) or 4946E (0.017-0.450) alleles. This demonstrates that the PxRyR I4790K mutation is currently the major contributing factor to chlorantraniliprole resistance in P. xylostella field populations within China. Our findings provide in vivo functional evidence for the causality of the I4790K mutation in PxRyR with high levels of diamide resistance in P. xylostella, and suggest that tracking the frequency of the I4790K allele is crucial for optimizing the monitoring and management of diamide resistance in this crop pest.

Effects of RDL GABA Receptor Point Mutants on Susceptibility to Meta-Diamide and Isoxazoline Insecticides in Drosophila melanogaster.

Ionotropic γ-aminobutyric acid (GABA) receptors in insects, specifically those composed of the RDL (resistant to dieldrin) subunit, serve as important targets for commonly used synthetic insecticides. These insecticides belong to various chemical classes, such as phenylpyrazoles, cyclodienes, meta-diamides, and isoxazolines, with the latter two potentially binding to the transmembrane inter-subunit pocket. However, the specific amino acid residues that contribute to the high sensitivity of insect RDL receptors to these novel insecticides remain elusive. In this study, we investigated the susceptibility of seven distinct Drosophila melanogaster Rdl point mutants against four meta-diamide and isoxazoline insecticides: isocycloseram, fluxametamide, fluralaner, and broflanilide. Our findings indicate that, despite exhibiting increased sensitivity to fluralaner in vitro, the RdlI276C mutant showed resistance to isocycloseram and fluxametamide. Similarly, the double-points mutant RdlI276F+G279S also showed decreased sensitivity to the tested isoxazolines. On the other hand, the RdlG335M mutant displayed high levels of resistance to all tested insecticides. Molecular modeling and docking simulations further supported these findings, highlighting similar binding poses for these insecticides. In summary, our research provides robust in vivo evidence supporting the idea that the inter-subunit amino acids within transmembrane M1 and M3 domains form the binding site crucial for meta-diamide and isoxazoline insecticide interactions. This study highlights the complex interplay between mutations and insecticide susceptibility, paving the way for more targeted pest control strategies.

Discovery of cyantraniliprole, a potent and selective anthranilic diamide ryanodine receptor activator with cross-spectrum insecticidal activity.

Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide range of pests from multiple insect orders. Here we report on the chemistry, biology and structure-activity trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial development.

Species differences in chlorantraniliprole and flubendiamide insecticide binding sites in the ryanodine receptor.

Anthranilic and phthalic diamides exemplified by chlorantraniliprole (Chlo) or cyantraniliprole (Cyan) and flubendiamide (Flu), respectively, are the newest major chemotype of insecticides with outstanding potency, little or no cross resistance with other classes and low mammalian toxicity. They are activators of the ryanodine (Ry) receptor (RyR)-Ca(2+) channel, based on Ca(2+) flux and electrophysiology investigations. The goal of this study is to define species differences in the degree and mechanisms of diamide selective action by radioligand specific binding studies at the [(3)H]Ry, [(3)H]Chlo and [(3)H]Flu sites. The [(3)H]Ry site is observed in muscle of lobster, rabbit and four insect species (Musca domestica, Apis mellifera, Heliothis virescens and Agrotis ipsilon) whereas the [(3)H]Chlo site is evident in the four insects and the [(3)H]Flu site in only the two lepidoptera (Agrotis and Heliothis). [(3)H]Ry binding is significantly stimulated by Chlo, Cyan and Flu with the insects (except Flu with Musca) but not the lobster and rabbit. [(3)H]Chlo binding is stimulated by Ry and Flu in Musca and Apis but not in the lepidoptera, while Flu and Cyan are inhibitory. [(3)H]Flu binding is strongly inhibited by Chlo and Cyan in Agrotis and Heliothis. [(3)H]Chlo and [(3)H]Flu binding are not dependent on added Ca(2+) or ATP in Heliothis and Agrotis whereas the other radioligand-receptor combinations are usually enhanced by Ca(2+) and ATP. More generally, there are species differences in the Ry, Chlo and Flu binding sites of the RyR that may confer selective toxicity and determine target site cross resistance mechanisms.

Chlorantraniliprole Residual Control and Concentration Determination in Cotton.

Studies were conducted in 2020 and 2021 at the Delta Research and Extension Center in Stoneville, MS, to determine the residual concentrations of chlorantraniliprole in cotton (Gossypium hirsutum, L.) leaves, as well as the concentrations in petals and anthers that developed after the time of application. Foliar applications of chlorantraniliprole were applied at four rates for leaves and two rates for petals and anthers at the second week of bloom. Additional bioassays were conducted to determine mortality of corn earworm (Helicoverpa zea, Boddie) in anthers. For the leaf study, plants were partitioned into three zones consisting of top, middle, and bottom zones. Leaf samples from each zone were analyzed for chemical concentrations at 1, 7, 14, 21, and 28 days after treatment (DAT). Residual concentrations, although variable, persisted through all sampling dates, rates, and zones tested. In this study, chlorantraniliprole remained detectable up to 28 DAT. Results from the cotton flower petal and anther studies detected concentrations of chlorantraniliprole in petals at 4, 7, 10, and 14 DAT, but no concentrations were detected in anthers. Therefore, no mortality of corn earworm was recorded in the anther bioassays. A series of diet-incorporated bioassays were conducted using concentrations previously found in the petal study to determine baseline susceptibilities of corn earworms and predicted mortality. Results from the diet-incorporated bioassays showed similar susceptibility in field and lab colony corn earworms. Concentrations of chlorantraniliprole could provide up to 64% control of corn earworm when feeding occurs on the petals.

Anthranilic Diamides Containing Monofluoroalkene Amide Linkers as Potential Insect RyR Activators: Design, Synthesis, Bio-evaluation, and Computational Study.

In order to develop anthranilic diamides with novel chemotypes, a series of anthranilic diamides with acrylamide linkers were designed and synthesized. The results of preliminary bioassays indicated that compounds with a monofluoroalkene amide linker (Z-isomer) exhibited good larvicidal activity against lepidopteran pests. The LC50 values of compound A23 against Mythimna separata and Plutella xylostella were 1.44 and 3.48 mg·L-1, respectively, while those of chlorantraniliprole were 0.08 and 0.06 mg·L-1, respectively. Compound A23 also exhibited the same level of lethal potency against resistant and susceptible strains of Spodoptera frugiperda at 50 mg·L-1. Compound A23 exhibited similar symptoms as chlorantraniliprole in test larvae. Comparative molecular field analysis was conducted to demonstrate the structure-activity relationship. Central neuron calcium imaging experiments indicated that monofluoroalkene compounds were potential ryanodine receptor (RyR) activators and activated calcium channels in both the endoplasmic reticulum and the cell membrane. Molecular docking suggested that A23 had a better binding potency to P. xylostella RyR than chlorantraniliprole. The MM|GBSA dG bind value of A23 with P. xylostella RyR was 117.611 kcal·mol-1. Monofluoroalkene was introduced into anthranilic diamide insecticides for the first time and brought a novel chemotype for insect RyR activators. The feasibility of fluoroalkenes as insecticide fragments was explored.

3D-QSAR-Based Molecular Design to Discover Ultrahigh Active N-Phenylpyrazoles as Insecticide Candidates.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III b and III y showed similar activity against M. separata as chlorantraniliprole (LC50 values: 0.21, 0.25, and 0.16 µg mL-1 respectively). Compounds III b exhibited a 3-fold higher potency against P. xylostella than chlorantraniliprole. For S. frugiperda, the potency of III a and III b was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III b can dock well with mutated P. xylostella RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III b was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.

Design, Synthesis, and Insecticidal Evaluation of N-Pyridylpyrazole Amide Derivatives Containing 4,5-Dihydroisoxazole Amide as Potential Ryanodine Receptor Activators.

Using the 4,5-dihydroisoxazol amide structure to expand the aliphatic amide moiety of chlorantraniliprole, a series of 28 novel N-pyridylpyrazolecarboxamide derivatives containing 4,5-dihydroisoxazol amide fragment were designed and synthesized. All target compounds had been properly characterized and confirmed by 1H NMR, 13C NMR, and HRMS, and the effects were evaluated against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The bioassay results indicated that most of the target compounds exhibited good insecticidal activities against M. separata and P. xylostella at 50 mg/L; especially, compound A4 showed an LC50 value of 3.27 mg/L against M. separata. Calcium imaging experiments indicated that the target compound A4 had a similar mechanism of action to chlorantraniliprole, causing an increase in the cytoplasmic Ca2+ concentration. The molecular docking revealed the possible binding mode of compound A4 with a ryanodine receptor.

The ryanodine receptor mutation I4728M confers moderate-level resistance to diamide insecticides in Spodoptera litura.

BACKGROUND: The common cutworm, Spodoptera litura (Fabricius), is one of the most widespread and destructive polyphagous pests in tropical and subtropical Asia. S. litura has evolved resistance to different insecticides, including diamide insecticides. Here, we identified a ryanodine receptor (RyR) mutation (I4728M) associated with target site resistance to diamides in a field-collected population of S. litura. The contribution of this mutation to diamide resistance was investigated through establishing a near-isogenic resistant strain of S. litura. RESULTS: The ND21 population of S. litura, collected from Ningde, Fujian province of China in 2021, exhibited 130.6-fold resistance to chlorantraniliprole compared to the susceptible NJ-S strain. S. litura RyR mutation I4728M, corresponding to Plutella xylostella RyR I4790M, was identified in the ND21 population. SlRyR I4728M mutation of ND21 was introgressed into a susceptible background strain (NJ-S) with marker-assisted backcrossing. The introgressed strain named ND21-R, which was homozygous for the mutant 4728M allele, shared about 94% of the genetic background with the NJ-S strain. ND21-R strain showed moderate levels of resistance to two anthranilic diamides (19.1-fold to chlorantraniliprole, 19.7-fold to cyantraniliprole) and the phthalic diamide flubendiamide (23.4-fold). Genetic analysis showed that chlorantraniliprole resistance was autosomal, incompletely recessive and tightly linked with SlRyR I4728M mutation in the introgressed ND21-R strain of S. litura. CONCLUSION: Identification of the I4728M mutation and its contribution to diamide resistance in S. litura will help develop allelic discrimination assays for resistance monitoring and guide resistance management practices for diamides in S. litura. © 2023 Society of Chemical Industry.

Design, synthesis, characterization and insecticidal screening of novel anthranilic diamides comprising acyl thiourea substructure.

BACKGROUND: Mosquito-borne pathogens constitute a major health problem worldwide. The extermination of the mosquito remains a significant issue in public health. Chemical insecticides have been used to control mosquitoes for decades. However, resistance has become a limiting factor for their control. The anthranilic diamide insecticides possess excellent insecticidal activities against Lepidoptera and its resistant strains by draining internal calcium stores on activating insect ryanodine receptors. However, the reports on the effect on mosquitoes are scarce and hence a series of novel anthranilic diamides comprising acyl thiourea substructure were synthesized and their insecticidal activities against three vector mosquito larvae namely, Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi were evaluated as per WHO protocol. Also investigated the morphological observations of treated larvae. RESULTS: Novel anthranilic diamides containing an acyl thiourea substructure were synthesized and structures were established by 1 H nuclear magnetic resonance (NMR), 13 C NMR, Fourier transform infrared (FTIR) and high-resolution mass spectrometry (HR-MS). Mosquito larvicidal activity of the title compounds 6-a-s revealed that compound 6-l exhibited marked larvicidal activities against C. quinquefasciatus and A. aegypti 3rd instar larvae with median lethal concentrations (LC50 ) values of 0.0044 mm and 0.0070 mm, respectively, for 48 hours of treatment. Compound 6-g exhibited larvicidal activity against An. stephensi with LC50 value of 0.0085 mm. Peculiar morphological alterations in the body of the treated larvae leading to death were observed on microscopic examination. CONCLUSION: Novel anthranilic diamides containing an acyl thiourea substructure were designed, synthesized and characterized. Their bioassay results demonstrated significant mosquito larvicidal activity with striking morphological alterations in the body, which should ensure forthcoming designs of highly active diamide derivatives as mosquito larvicides. © 2022 Society of Chemical Industry.

Novel diamides inspired by protein kinase inhibitors as anti-Trypanosoma cruzi agents: in vitro and in vivo evaluations.

Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi. The involvement of serine-/arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC50/IC50 in two in vitro models. The most active compound, 3j, was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results: 3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruzi in vitro and in vivo.

Diarylamine-Guided Carboxamide Derivatives: Synthesis, Biological Evaluation, and Potential Mechanism of Action.

Diarylamines are a class of important skeleton widely existing in drugs or natural products. To discover novel diarylamine analogues as potential drugs, two series of diamide and carboxamide derivatives containing diarylamine scaffold were designed, synthesized and evaluated for their potential cytotoxic activities. The bioassay results indicated that some of the obtained compounds (C5, C6, C7, C11) exhibited good cytotoxic effect on cancer cell lines (SGC-7901, A875, HepG2), especially, compound C11 present significantly selective proliferation inhibition activity on cancer and normal cell lines (MARC145). In addition, the possible apoptosis induction for highly potential molecules was investigated, which present compound C11 could be used as novel lead compound for discovery of promising anticancer agents.