Search

As part of our ongoing antileishmanial structure–activity relationship study, a structural simplification of the 3‐nitroimidazo[1,2‐a]pyridine ring to a 5-nitroimidazole moiety was conducted. A series of novel 2,4-disubsituted 5-nitroimidazole derivatives, including the 5-nitroimidazole analog of Hit A and the 4-phenylsulfonylmethyl analog of fexinidazole, were obtained by using the vicarious nucleophilic substitution of hydrogen (VNS) reaction, to substitute position 4, and by using the tetrakis(dimethylamino)ethylene methodology to modulate position 2. The molecular structures of eight novel 5-nitroimidazoles were characterized by 1H NMR, 13C NMR, LC/MS, and HRMS. The in vitro antileishmanial activity of these compounds was evaluated against the promastigote form of Leishmania infantum and their influence on cell viability was assessed on the human hepatocyte HepG2 cell line. The 4-phenylsulfonylmethyl analog of fexinidazole showed the best selectivity index of the series, displaying good activity against both the promastigote form of L. infantum (EC50 = 0.8 µM, SI > 78.1) and the promastigote form of Leishmania donovani (EC50 = 4.6 µM, SI > 13.6), and exhibiting low cytotoxicity on the HepG2 cell line (CC50 > 62.5 µM).

This paper aims to investigate the syntactic mechanisms behind the grammaticalization and lexicalization of saying verbs from the perspectives of linguistic typology and comparative syntax. It is proposed that, in addition to the evolution from lexical categories to functional categories along the clausal spine, there is also a mechanism that merges the verb shuo 'say' into a neighboring phrase/clause, which is in turn reanalyzed as either an adverbial or a complement depending on its morpho-syntactic makeups. To use an idiom, this means that "It is easier to touch the moon at a pavilion near the waterfront." The result is a plethora of usages such as quotative, clause-typing, evidential, subjunctive, concessive, topic- marking, and enumerative. They show up at various levels of syntactic structure, while heading the corresponding functional projections. At the final stage of its evolution, shuo may undergo extreme semantic bleaching and become a linker, which very often can be dropped freely. We substantiate this observation by drawing evidence from Classical Chinese, Formosan languages, and the grammaticalization of shi 'be' in Modern Mandarin, which can be seen as an excellent example of convergent evolution. [ABSTRACT FROM AUTHOR]

In this work, the structural design of a structure-simplified parallel Delta robot is presented, by considering the kinetostatics, kinematic dexterity and workspace. An approach to normalize the dimensionally inhomogeneous Cartesian stiffness matrix is introduced, and a stiffness evaluation index is defined by means of the singular value decomposition of homogenized stiffness matrix, which is used in the design optimization in turn. A multi-objective design optimization problem is formulated to provide the optimal solutions of different sets of geometric parameters. A set of parameters is selected to lay out the robot, and the tested specifications show the good performances, although the speed is not so high as the commercial FlexPicker and Quattro. A comparative study is carried out between the proposed and original Delta robots by observing joint dynamics, showing that the modified robot structure can improve the robot dynamics. The presented work turns out that the proposed robot is applicable to the pick-and-place operations without high-precision requirement in most industrial sectors. [ABSTRACT FROM AUTHOR]

The synthesis of the originally proposed structure of (±)-nicotlactone A, a potent antiviral lignan with three continuous chiral centers, is reported in 5 steps from methyl acrylate. The key steps of the synthesis included an In-catalyzed regioselective allylation and a Mn-catalyzed Mukaiyama hydration reaction. Our synthetic strategy also enabled us to get the other three epimers and investigate the structure–activity relationship. The NMR data of the synthesized compounds do not match that of the isolated sample, indicating that the structure of nicotlactone A remains to be reassigned. All the synthetic target compounds were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. Bioassay results indicated that (±)-8-demethylnicotlactone A displayed similar anti-TMV activity to the commercial agent ningnanmycin, thus being a promising candidate or lead compound for developing novel antiviral agents in crop protection. [ABSTRACT FROM AUTHOR]

Static and dynamic behaviors of the human spine in response to internal and external loads may be useful in future building design. The new structure was made by simplification in structure parts more than the previous validated material simplifications of Finite Element (FE) of one motion segment of the human lumbar spine (L3/L4). The study showed the anatomical and mechanical properties of this model were adapted to validated previously models by having fewer materials and stress amount. This validated simplified structure by having the natural process may be useful to achieve adaptable, sustainable, and sensible future structures for several disciplines. Simplification of human lumbar spine structure more than material simplifications. Simplified lumbar structure for prosthesis, implants, building joints & structures. Having fewer materials, less stress & simple form by simplifying lumbar structure. Simplified lumbar structure by being resistant against internal & external response. Sustainable, sensible & adaptable structure by inspiration of the natural process. [ABSTRACT FROM AUTHOR]

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC 50 value of 0.13 μM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC 50 , along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 μg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin . Notably, the syn -diastereomer ( syn - 3g ) exhibited superior antiviral activity compared to the anti -diastereomer ( anti - 3g ). Mechanistic studies revealed that syn - 3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g , with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

The sustainable production and utilization of lignocellulose biomass are indispensable for establishing sustainable societies. Trees and large-sized grasses are the major sources of lignocellulose biomass, while large-sized grasses greatly surpass trees in terms of lignocellulose biomass productivity. With an overall aim to improve lignocellulose usability, it is important to increase the lignin content and simplify lignin structures in biomass plants via lignin metabolic engineering. Rice ( Oryza sativa ) is not only a representative and important grass crop, but also is a model for large-sized grasses in biotechnology. This review outlines progress in lignin metabolic engineering in grasses, mainly rice, including characterization of the lignocellulose properties, the augmentation of lignin content and the simplification of lignin structures. These findings have broad applicability for the metabolic engineering of lignin in large-sized grass biomass plants., Competing Interests: Conflict of interestThe author has no conflicts of interest to declare., (© 2024 Japanese Society for Plant Biotechnology.)

Attached outlets are integral components of arch dams to discharge flood. However, they are usually neglected in the current seismic analysis of arch dams for simplicity. This paper aims to analyze the effect of attached outlets on the nonlinear seismic response of arch dams. For this purpose, a 235 m high arch dam is analyzed as a case study. The results indicate that the effect of attached outlets on the seismic response of arch dams depends on the ground motion intensity. For the ground motions with a low peak ground acceleration (PGA), the effect of attached outlets on the concrete damage is slight and local, which is consistent with the existing perception. However, as the ground motion intensity increases, their effect extends to the entire dam body. In contrast, the influence of attached outlets on the joint opening is typically observed at the middle contraction joints. Furthermore, the model analysis demonstrates that the inertia effect of attached structures is the primary contribution to these phenomena. Finally, a simplified simulation approach is used for incorporating the influence of attached outlets by coalescing the mass to the dam surface. • The effect of attached outlets on the nonlinear response of arch dams is investigated. • Mechanism of the attached outlets' effect is analyzed. • A simplified simulation approach of the attached structures is investigated. [ABSTRACT FROM AUTHOR]

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design. For large or complex lead compounds, structural simplification is helpful to discover drug-like molecules with improved synthetic accessibility and favorable pharmacodynamic/pharmacokinetic profiles. Image 1 [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Cryptococcus neoformans is the leading cause of cryptococcal meningitis, which is associated with high mortality due to lack of effective treatment. Herein a series of tricyclic isoxazole derivatives with excellent anti-cryptococcal activities were identified by structural simplification and scaffold hopping of antifungal natural product sampangine. Particularly, compound 8a showed promising features as an anti-cryptococcal lead compound. It was highly active against C. neoformans (MIC 80 = 0.031 μg/mL), which was more potent than fluconazole and voriconazole. Moreover, compound 8a showed potent fungicidal activity and had potent inhibitory effects against important virulence factors (i.e. biofilm, melanin and urease) of C. neoformans. Preliminary antifungal mechanism investigation revealed that compound 8a induced apoptosis of C. neoformans cells and arrested the cell cycle at the G1/S phase. [ABSTRACT FROM AUTHOR]

Lignocellulose polysaccharides are encrusted by lignin, which has long been considered an obstacle for efficient use of polysaccharides during processes such as pulping and bioethanol fermentation. Hence, numerous transgenic plant lines with reduced lignin contents have been generated, leading to more efficient enzymatic saccharification and forage digestion. However, lignin is also a potential feedstock for aromatic products and an important direct-combustion fuel, or a by-product fuel in polysaccharide utilization such as pulping and bioethanol production. For aromatic feedstock production, the complicated structure of lignin along with its occlusion within polysaccharide matrices makes lignin utilization intractable. To alleviate these difficulties, simplification of the lignin structure is an important breeding objective for future high-value utilization of lignin. In addition, higher lignin contents are beneficial for increasing heating values of lignocellulose, because lignin has much larger heating values than polysaccharides, cellulose and hemicelluloses. Structural modification of lignin may also be effective in increasing heating values of lignocellulose biomass, because the heating value of p-hydroxyphenyl lignin is highest, followed by those of guaiacyl lignin and of syringyl lignin in this order. Herein, recent developments for augmenting lignin contents and for lignin structural modifications, to improve its utilization by metabolic engineering, are outlined. [ABSTRACT FROM AUTHOR]

The present paper discusses the occurrence, structure, and complexity of the postmodifier in the Nigerian English noun phrase (NP) showing tendencies for structural simplification. It also compares its findings with patterns in British, Ghanaian, Singaporean, Honk Kong varieties. The paper shows how variables representing syntactic function, register, and weight shed light on specific contexts where we might or might not find (1) NP with or without a postmodifier (2) a clausal or phrasal postmodifier, and (3) a simple or a complex postmodifier. In addition, the paper shows that the extent of variation among different varieties of English is dependent on variables crucial to the construction choices being investigated. For instance, in (1), a postmodifier is realised while no postmodifier is realised in (2). (1) My car which I just bought last week has been stolen, and (2) My car has been stolen.The NP in (1) is structurally complex because it realises the clausal type of post modifier, 'which I just bought last week'. Meanwhile in (2), the NP (the car) lacks a postmodifier. In other words, the occurrence viz-a-viz non-occurrence of a postmodifier contributes to the overall structural and semantic complexity of the entire noun phrases, irrespective of the syntactic positions of the NP. Quantitative analyses of 8897 NPs indicate that in Nigerian NPs, a postmodifier is more unlikely to occur (61 %) than not (39 %). Further analyses show that prepositional phrase (57 %), rather than clause (32 %) or adjective (9 %) or adverbials (2 %), is the most preferred structural postmodifier type. It is also shown that realised postmodifiers are more likely to be structured in two-to-four words (51 %) than four-words above. As for the predictive strength of variables studied, syntactic function is found to edge register in asserting influence and explaining different scenarios and contexts where we might or might not find a postmodifier, together with its structural type and weight. In other words, register, which is reputed as a significant indicator of structural variation (Biber, 2007; De Haan, Pieter. 1993. Sentence Length in Running Text. In Souter, C. & E. Atwell (), Corpus-Based Computational Linguistics, 147–161. Amsterdam: Rodopi; Schilk and Schaub, 2016) is outweighed by syntactic function. The study further attests that significant structural simplification is largely present in the postmodifier structure of the Nigerian English noun phrase. [ABSTRACT FROM AUTHOR]

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l , 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2 μg/mL) and three resistant strains (0.25–4 μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents. [ABSTRACT FROM AUTHOR]

Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0-A31 and B0-B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC 50 value of 130.4 μg/mL, which was superior to that of commercial ningnanmycin (EC 50 = 202.0 μg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC 50 value of 43.8 μg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper . This research lays a solid foundation for the utilization of furofuran lignans in crop protection.

In a recent investigation carried out on a panel of trimethoxybenzanilides, we showed that the formation of an intramolecular hydrogen bond is a key element for tuning P-gp inhibitory activity. In this study, we designed new structurally simplified trimethoxy benzamides ( 5- 17, Table [ABSTRACT FROM AUTHOR]

As an important family member of Toll-like receptors (TLRs), TLR2 can recognize various pathogen-associated molecular patterns (PAMPs) such as bacteria and viral components. Accumulating evidence demonstrates that TLR2 agonists play a critical role in cancer immunotherapy and infectious diseases. Diprovocim is the most potent small molecule TLR2 agonist known, showing remarkably immune adjuvant activity in mice. However, the further clinical research and development of Diprovocim was hampered because of its structural complexity as well as high molecular weight. Here, we designed and synthesized 21 structurally simplified derivatives of Diprovocim, performed their TLR2 agonistic activities by HEK-Blue hTLR2 SEAP assay, and evaluated the toxicity in two human normal cell lines. Compounds B3–B4 and B9–B12 with excellent TLR2 agonistic activity were found through the structure-activity relationship study. Among them, diastereomer B10 and B12 substituted (S)-2-phenylcyclopropylamide side chain of Diprovocim with simple (R)- and (S)- n -butyl groups exhibited comparable TLR2 agonistic activities with EC 50 values of 35 nM and 39 nM, respectively. ELISA and western blot experiments on THP-1 cells showed that B10 and B12 displayed remarkable immunostimulatory activity in the release of various inflammatory cytokines through activating MyD88-dependent NF-κB and MAPK signaling pathways. Importantly, B10 and B12 have less structural complexity and better safety compared to Diprovocim, and the chiral center of right pyrrolidine ring has negligible influence on TLR2 activition. Our study provides simplified Diprovocim derivatives with high agonistic activity, providing a clue to further optimize Diprovocim. [Display omitted] • We designed and synthesized 21 simplified Diprovocim derivatives and indicated introduction of alkyl chain would be useful. • Diastereomer B10 and B12 exhibited comparable TLR2 agonistic activities with EC 50 values of 35 nM and 39 nM, respectively. • B10 and B12 induced the release of inflammatory cytokines by activating MyD88-dependent NF-κB and MAPK signaling pathways. • B10 and B12 have less structural complexity and better safety compared to Diprovocim. [ABSTRACT FROM AUTHOR]

A series of quinoline derivatives were designed and synthesized by the structural simplification of cryptolepine and evaluated for their fungicidal activity against six phytopathogenic fungi. Most of these compounds exhibited remarkable activities against Botrytis cinerea in vitro . Among them, compounds A18 and L01 showed superior antifungal activity. Significantly, compared to cryptolepine, compound A18 exhibited broad-spectrum inhibitory activities against B. cinerea , Sclerotinia sclerotiorum , Rhizoctonia solani , Phytophthora capsica , Magnaporthe oryzae , and Fusarium graminearum with the respective EC 50 values of 0.249, 1.569, 3.915, 0.505, 0.246, and 4.999 μg/mL. Compound L01 displayed the best antifungal activity against B. cinerea with an EC 50 value of 0.156 μg/mL. Preliminary mechanistic studies showed that compound A18 could inhibit spore germination, affect the permeability of the cell membrane, increase the content of reactive oxygen species, and affect the morphology of hyphae and cells. Moreover, compound A18 showed excellent in vivo protective effect against B. cinerea , which was more potent than pyrimethanil and equitant to cryptolepine. These results evidenced that compound A18 displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.

The natural product oridonin has the potential to be a broad-spectrum antineoplastic agent. To develop oridonin analogues with high potency, a series of novel oridonin analogues were designed and synthesized by removing the multiple hydroxyl groups of parent compound. The representative analogues 14 , 19 , and 26 exhibited potent anticancer effects against K562, MDA-MB-231, SMMC-7721, and MCF-7 cells. Further structural modification on their 14-OH generated more potent derivatives 16n , 21d , and 28d respectively, in which the IC 50 value of compound 16n was 50-fold more potent than parent oridonin in K562 cells. Furthermore, compound 16n significantly induced the cell cycle arrest of K562 cells at the G2 phase and increased the fraction of apoptotic cells. Importantly, compounds 16n , 21d , and 28d exhibited good antitumor activities in H22 allograft mice in vivo. These results suggest that compounds 16n , 21d , and 28d deserve further development as promising candidates for the treatment of cancers. [Display omitted] • The novel derivatives were obtained by simplifying the core structure of oridonin. • Compound 16n was 50 times more potent than oridonin in K562 cells. • Compound 16n showed better cytotoxicity selectivity than oridonin in vitro. • Compound 16n significantly suppressed tumor growth without affecting body weight. [ABSTRACT FROM AUTHOR]

Abstract: The modular modeling paradigm facilitates the efficient building, verification and handling of complex system models by assembling them from general-purpose component models. A drawback of this paradigm, however, is that the assembled system models may have excessively complex structures for certain purposes due to the amount of detail in the component models that has been introduced to promote modularity. For example, a multibody system can be modeled using generic rigid-body models with 6 degrees-of-freedom (DoF) to represent the components of the system, but then constraints have to be added to the model to match the DoF of the system. This work presents a structural simplification technique that can detect such unnecessary complexities in a modular bond-graph system model and eliminate them without compromising accuracy. To this end, the activity concept in the literature is extended to define “inactivity” for junction elements, and simplification is obtained by detecting and eliminating inactive junction elements and by propagating the implications. It is shown by example that this simple idea can result in models that are conceptually and computationally more efficient than the original modular models. The realization-preserving and input-dependent characteristics of this approach are highlighted. [Copyright &y& Elsevier]

[Display omitted] Alzheimer's disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins β-amyloid (Aβ) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy. [ABSTRACT FROM AUTHOR]

The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro , affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Removal of dispensable substructures of the lead molecule tetrandrine increases antiproliferative properties against cancer cells and impairs proangiogenic signaling of endothelial cells to a greater extent than tetrandrine. Simultaneously, toxic effects on non-cancerous cells are reduced, allowing in vivo administration and revealing a TPC2 inhibitor with antitumor efficacy in mice. Hence, our study unveils TPC2 as valid target for cancer therapy and provides easily accessible tetrandrine analogs as a promising option for effective pharmacological interference. [Display omitted] • TPC2 knockout reduces HCC cell proliferation and prevents tumor growth • TPC2 deficiency alters the metabolic phenotype • Easily accessible, potent inhibitors with favorable drug-likeness were developed Müller et al. describe that genetic TPC2 knockout reduces cell proliferation in vitro , alters cellular energy metabolism, and effectively suppresses tumor growth in vivo , suggesting that this lysosomal ion channel represents a suitable target for cancer therapy. Concurrently, a potent TPC2 inhibitor with antitumor efficacy was developed. [ABSTRACT FROM AUTHOR]

It is shown how a multicompartmental infectious disease model can be systematically examined for reduction of structural complexity. For steadystate situations, four basic rules are proposed for eliminating components of flow-lines, whole flow-lines, and compartments, plus combining compartments. An application to a typhoid fever model allows calculations to be done on a pocket calculator. The approach could be particularly important in developing countries. [ABSTRACT FROM AUTHOR]

[Display omitted] Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro- β -carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45 , which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G 2 /M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure–activity relationships of evodiamine. [ABSTRACT FROM AUTHOR]

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC 50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC 50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model. Image 1 •A series of 2-azabicyclo[3.2.1]octane derivatives was designed and synthesized. •Antitumor activities of these compounds were evaluated in six cancer cell lines. •Compound 14t induced G1/S cell cycle arrest and apoptosis in LoVo and SW620 cells. •Compound 14t significantly reduced the volumes and size of colon tumors in mice. [ABSTRACT FROM AUTHOR]

• A new series of sulfonamides bearing a diaryl ether scaffold were designed and prepared via structural simplification. • N -(3,5-Dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzenesulfonamide (3f), a representative target compound, demonstrated potent inhibitory activities against both mitochondrial complex II and complex III. • Computational simulations of 3f in the present study were carried out to clarify its possible binding mode with mitochondrial complex II and complex III. Mitochondrial complex II and complex III are two promising targets for the development of numerous pharmaceuticals and pesticides. Although tremendous inhibitors of either complex II or complex III were identified, compounds which are capable of prohibiting the activities of both complexes have been rarely reported. Since multi-target drugs can interact with several drug targets simultaneously, we were keen on discovering new and potent dual-target inhibitors of both complex II and complex III. Therefore, a new series of structurally simplified sulfonamides bearing a diaryl ether scaffold were designed and synthesized in this paper. Afterwards, the biological activities of the newly synthesized compounds were evaluated. The results implied that several compounds demonstrated outstanding potency against succinate-cytochrome c reductase (SCR, a mixture of complex II and complex III). Further studies confirmed that N -(3,5-Dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzenesulfonamide (3f) , a representative compound herein, was identified as a dual-target inhibitor of both complexes. Furthermore, computational simulations were also performed to have a better understanding about binding of 3f to the enzyme complexes, which concluded that 3f should bind to complex II and the Q o site of complex III. Consequently, we harbor the idea that this work can be beneficial for the synthesis and discovery of more dual- or multi-target inhibitors. [ABSTRACT FROM AUTHOR]

Several studies have been conducted to understand the dynamic of primary metabolisms in fruit by translating them into mathematics models. An ODE kinetic model of sugar metabolism has been developed by Desnoues et al. (2018) to simulate the accumulation of different sugars during peach fruit development. Two major drawbacks of this model are (a) the number of parameters to calibrate and (b) its integration time that can be long due to non-linearity and time-dependent input functions. Together, these issues hamper the use of the model for a large panel of genotypes, for which few data are available. In this paper, we present a model reduction scheme that explicitly addresses the specificity of genetic studies in that: (i) it yields a reduced model that is adapted to the whole expected genetic diversity (ii) it maintains network structure and variable identity, in order to facilitate biological interpretation. The proposed approach is based on the combination and the systematic evaluation of different reduction methods. Thus, we combined multivariate sensitivity analysis, structural simplification and timescale-based approaches to simplify the number and the structure of ordinary differential equations of the model. The original and reduced models were compared based on three criteria, namely the corrected Aikake Information Criterion (AIC C ), the calibration time and the expected error of the reduced model over a progeny of virtual genotypes. The resulting reduced model not only reproduces the predictions of the original one but presents many advantages including a reduced number of parameters to be estimated and shorter calibration time, opening new promising perspectives for genetic studies and virtual breeding. The validity of the reduced model was further evaluated by calibration on 30 additional genotypes of an inter-specific peach progeny for which few data were available., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)