Synthesis,characterization, antibacterial activity,and molecular docking of novel dicyanodihydrofuran-based push–pull fluorophores

Novel push–pull fluorescent molecules based on dicyanodihydrofuran that had marked molar extinction coefficients were created and described. The fluorophores were synthesized using the Knoevenagel condensation in arid pyridine at room temperature and acetic acid as a catalytic agent. In addition, a condensation reaction was performed for the activated methyl-containing dicyanodihydrofuran with a 3° amine-containing aromatic aldehyde. The molecular structures for the synthesized fluorophores were determined using various spectral techniques such as ¹H or ¹³C nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR) spectroscopy, and C, H, N analysis. Ultraviolet–visible (UV–vis) absorption and emission spectra of the prepared fluorophores revealed a high extinction coefficient, which was monitored to be affected by the type of the aryl (phenyl and thiophene)–vinyl bridge in conjugation with the 3° amine donor moiety. The substituents bonded to the tertiary amine, aryl, and alkyl groups, were found to affect the maximum absorbance wavelength. In addition, the synthesized dicyanodihydrofuran analogues were investigated to determine their antimicrobial effectiveness. Derivatives 2b , 4a , and 4b showed reasonable activity towards Gram-positive(+ve) bacteria rather than Gram-negative(−ve) bacteria relative to an amoxicillin drug reference. In addition, a molecular docking stimulation was performed to explore the binding interactions (PDB code: 1LNZ).     

Synthesis,antioxidant, and molecular docking of new fluorescent (4-alkoxyphenyl)-nitrothiophene compounds

New fluorescent 4-alkoxyphenyl-nitrothiophene compounds 4a–d bearing diverse alkoxyl tails are described. The synthetic strategy was simply accomplished by alkali-assisted alkylation of 4-(5-nitrothiophen-2-yl)phenol ( 3 ) with propyl, hexyl, nonyl, and/or dodecyl iodide. The molecular structures were determined using infrared (IR), ¹H NMR, and mass spectroscopy. Ultraviolet–visible (UV–vis) absorption and emission spectra of the produced 4-alkoxyphenyl-nitrothiophenes revealed considerable extinction coefficients, which were shown to be controlled by the thiophene bridge in conjugation with the alkoxy donor moiety. It was found that the maximum absorbance wavelength was affected by the alkoxyl group-bonded substituents. The antioxidant efficiency obtained from the 4-alkoxyphenyl-nitrothiophene hybrids was excellent compared with that widely used drugs [butylated hydroxytoluene (BHT) and vitamin C]. Unlike 2-(4-[dodecyloxy]phenyl)-5-nitrothiophene hybrid 4d , which has made solid claims about the good effect of its reference drugs and vitamins, Docking investigations of the prepared 4-alkoxyphenyl-nitrothiophene hybrids towards the selected 5IKQ protein revealed impressive coordination and antioxidant effectiveness.     

Copper(I)-catalysed synthesis of symmetrical perfluoroterphenyl analogues; fluorescence,antioxidant and molecular docking studies

Pentafluoroaryl analogues have been found to exhibit para specific nucleophilic aromatic substitution (S_NAr). Herein, we describe the use of S_NAr chemistry to create luminous perfluorinated symmetrical terphenyls. Both of S_NAr chemistry and copper(I)-catalysed decarboxylative cross-coupling were applied for the synthesis of the perfluorinated symmetrical terphenyls in high yields from the corresponding derivatives of aryl iodide and potassium salt of fluorobenzoate. A series of perfluorinated symmetrical terphenyls with different para alkoxy chains were synthesized. The synthesized perfluorinated terphenyl adducts were confirmed via elemental analysis, Fourier-transform infrared (FTIR), proton (¹H) carbon-13 (¹³C) and fluorine-19 (¹⁹F) nuclear magnetic resonance (NMR) spectra. The absorbance and fluorescence spectra showed solvatochromic activities. The new synthesized fluoroterphenyl hybrids were screened against antioxidant inspection over DPPH (2,2-diphenyl-1-picrylhydrazyl) performance, in assessment of vitamin C and butylated hydroxytoluene (BHT) as standard drugs exposed that fluoroterphenyl hybrid covering decyl hydrocarbons exhibited highest effectiveness through half maximal inhibitory concentration (IC₅₀) values of 21.74 μg/ml. Additionally, molecular docking procedures of the synthesized fluoroterphenyl hybrids were employed by using protein data bank (PDB ID: 5IKQ). The docking simulation displayed convenient and recognized findings with the antioxidant examination.     

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis,docking studies and investigation of anti-inflammatory,ulcerogenic liability and analgesic activities

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC₅₀s of 0.75–70.50 μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.     

The manipulation mechanism of “push–pull” habitat management strategy and advances in its application

The “push–pull” habitat management strategy, as a new powerful and effective tool in integrated pest management (IPM), uses a combination of behavior-modifying stimuli to manipulate the distribution and abundance of pests and/or their natural enemies for pest control. In the “push–pull” strategy, pests are repelled or deterred away from the protected resource (push) by stimuli that disturb the host location and modulate the host become unattractive or unsuitable for the feeding and oviposition of pests. By using highly attractive stimuli, the target pests are simultaneously attracted (pull) to the specific source in which they are subsequently concentrated, facilitating their elimination and leaving the protected resource. Since stimuli usually are nontoxic, either “push” or “pull” components, the strategy is usually companied by population-reduced methods, such as using insecticides, exploiting nature enemies, and placing traps. Among them, methods of biological control are the most preferred. The “push–pull” strategies maximize efficacy of behavior-modifying stimuli through the additive and synergistic effects of integrating the use of methods for population reduction. In this review, the principles of the “push–pull” strategy were firstly described, then the potential behavior-modifying stimuli for “push” and “pull” components were introduced. The stimuli for use in “push–pull” strategies primarily include visual cues and chemical cues (synthetic or plant- or insect-derived semiochemicals). Visual stimuli, repellent and trap plants, host and non-host volatiles, insect pheromones, and antifeedants and oviposition deterrents are usually applied as the potential stimuli in the “push–pull” strategy for pest control. The stimuli are grouped as long-range stimuli and short-range stimuli. In addition, we also summarize models of “push–pull” habitat management strategy, such as agriculture, horticulture and forestry, of pest control and some successful case studies in applying of “push–pull” strategy and its potential ecological benefits. The “push–pull” technology (PPT), so far the most effective “push–pull” strategy in practice by farmers, developed for management of both stemborers and Striga hermonthica in maize-based farming system in eastern Africa were reviewed. The PPT uses an intercrop of repellent plants and border crops of attractive trap plants. Stemborer moths are effectively repelled away from the maize crop (push) by Desmodium and molasses grass, and are subsequently attracted (or trapped) to (pull) by the Napier grass and Sudan grass which emit the green leaf volatiles (GLVs) showing attractant properties. Finally, the problems in current research and future perspectives of the “push–pull” habitat management strategy are discussed in the present paper.     

Design and synthesis of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids and their anti-cancer evaluation

A new series of amide derivatives of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids (14a–g) were synthesized and their chemical structures were confirmed by ¹H, ¹³C NMR and mass spectral data. Further, all the synthesized Acetamidobenzofuranone-podophyllotoxin hybrids were evaluated for in vitro cytotoxic activity against a panel of four human cancer cell lines i.e., human breast (MCF-7, MDA MB-231), lung (A549), and prostrate (DU-145). Among benzofuranone-podophyllotoxin hybrid compounds, 14b and 14e were exhibited more potent activity than standard drug and 14c and 14f were showed anticancer activity equivalent to etoposide.     

Differential response of antioxidant enzymes in leaves of necrotic wheat hybrids and their parents

The leaves of necrotic hybrid of wheat ( Triticum aestivum L.) exhibited high superoxide content associated with increased lipid peroxidation and membrane damage in earlier studies (Khanna-Chopra et al. 1998, Biochem Biophys Res Commun 248: 712–715; Dalal and Khanna-Chopra 1999, Biochem Biophys Res Commun 262: 109–112). In the present study, we investigated the activities of the antioxidant enzymes in the leaves of necrotic wheat hybrids, Kalyansona×C306 (K×C) and WL711×C306 (WL×C) and their parents at different developmental stages. The K×C hybrid exhibited more severe necrosis than WL×C. In K×C, superoxide dismutase (SOD) activity showed no increase over the parents, while WL×C showed an early increase, but it was possibly insufficient to scavenge increased superoxide. Activities of guaiacol peroxidase, ascorbate peroxidase and glutathione reductase were enhanced, while catalase exhibited a decrease in activity, with the appearance of visible necrosis in both the hybrids. The isozyme profile of the antioxidant enzymes was similar in the hybrids and their parents. One existing isoform of guaiacol peroxidase showed an early appearance in the hybrid and increased in intensity with the progression of necrosis. The results reveal a differential response of antioxidant enzymes in necrotic wheat hybrids as compared to their parents. The response differed in magnitude at developmental stages of the leaves, which might be related to the intensity of necrosis expressed by the hybrids.     

Synthesis and antioxidant activities of some new triheterocyclic compounds containing benzimidazole,thiophene, and 1,2,4-triazole rings

Abstract

Various triheterocyclic compounds containing benzimidazole, thiophene, and 1,2,4-triazole rings (3–6) were synthesized and screened for their antioxidant activities. The structures of the synthesized compounds (2–6) were judged by ¹H NMR, ¹³C NMR, elemental analysis, and LC-MS spectral data. Antioxidant activities of the synthesized compounds (2–6) were determined with CUPric Reducing Antioxidant Capacity (CUPRAC), ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)/persulfate, and DPPH (1,1-diphenyl-2-picrylhydrazyl) assays. Most of the compounds showed a significant antioxidant activity and especially, compound 5c showed very good SC₅₀ value for DPPH method and compound 5h exhibited very high scavenging activity to ABTS method.     

Design,synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents

A series of estradiol–chlorambucil hybrids was synthesized as anticancer drugs for site-directed chemotherapy of breast cancer. The novel compounds were synthesized in good yields through efficient modifications of estrone at position 16α of the steroid nucleus. The newly synthesized compounds were evaluated for their anticancer efficacy in different hormone-dependent and hormone-independent breast cancer cell lines. The novel hybrids showed significant in vitro anticancer activity when compared to chlorambucil. Structure–activity relationship (SAR) reveals the influence of the length of the spacer chain between carrier and drug molecule.     

Variability of oxidative stress biomarkers in hemodialysis patients

Abstract

Oxidative stress biomarkers may have a role in the future to assist clinical decisions regarding the use of antioxidant therapies and their efficacy. The aims of this study were to evaluate the within and between-individual variability of plasma oxidative stress biomarkers and investigate factors affecting their variability. Plasma F2-isoprostanes and protein carbonyls were measured in 14 hemodialysis patients every 2 weeks for 10 weeks. Within-individual coefficients of variation (CVs) were isoprostanes?=?30.4% (range?=?6.1–66.7%) and protein carbonyls?=?16.3% (8.4–29.5%). Between-individual CVs were isoprostanes?=?34.4% (28.9–40.2%) and protein carbonyls?=?19.5% (15.6–24.5%). There were no significant (p?>?0.05) relationships between the oxidative stress biomarkers and dietary antioxidant intake, medications, clinical and demographic parameters.     

Analysis of myogenesis by somatic cell hybridization : I. Myogenic competence of homotypic hybrids derived from rat L6 myoblasts

Several authors have described the extinction of myogenic competence in hybrids produced by fusion of myogenic and non-myogenic cells. Interpretations of such experiments rest upon the assumption that extinction does not occur with any appreciable frequency as a non-specific consequence of the cell hybridization process itself. In order to test this assumption we have analyzed the myogenic competence of over 140 independent homotypic hybrid clones produced by PEG-mediated fusion of rat L6 myoblasts. Based upon an evaluation of myotube formation in hybrid colonies, we demonstrate that 99% of primary hybrid clones are myogenic. The fact that 97% of secondary hybrid colonies also differentiate indicates that myogenic competence is a stable characteristic of the hybrids. Four hybrid clones were isolated and expanded for analyses of chromosome numbers, myotube formation, creatine kinase activities, and microfluorimetric DNA determinations of myotube nuclei. Our results demonstrate that polyploid homotypic hybrid cells produced by fusion of non-neoplastic, developmentally determined rat myoblasts retain and express their program of differentiation. This work provides a foundation for future studies which will investigate the expression of myogenic properties in hybrids between myogenic and non-myogenic cells.     

Design,synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones

A series of novel pyrazole integrated benzophenones (9a–j) have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of the regioisomers 6 and 7 were determined by 2D ¹H–¹H COSY, ¹H–¹³C HSQC and ¹H–¹³C HMBC experiments. The newly synthesized compounds (9a–j) were evaluated for in vivo anti-inflammatory activity by carrageenan paw edema in rats and in vitro COX-1/COX-2 inhibition and antioxidant potential. Among the synthesized compounds, compounds 9b, 9d and 9f, were found to be active anti-inflammatory agents in addition to having potent antioxidant activity.     

Response of ground-dwelling arthropods to a 'push–pull' habitat management system: spiders as an indicator group

Abstract Studies were conducted to assess the numerical response of ground‐dwelling arthropods to a habitat management system (‘push–pull’) developed to control maize stemborers using spiders (Araneae) as an indicator group. In this cropping system, maize is intercropped with a stemborer moth‐repellent (push) plant while an attractant trap crop (pull) is planted around this intercrop. Two study sites in western Kenya and one site at the Grain Crops Institute of the Agricultural Research Council in Potchefstroom, South Africa, were sampled. Treatments comprised a maize monocrop and an intercrop of maize and desmodium, Desmodium uncinatum Jacq., with Napier grass, Pennisetum purpureum (Schumach), as a trap crop around the field (‘push–pull’) in each site. Experiments were laid out in a completely randomized design with four replications at each site. Ground‐dwelling spiders were sampled using a combination of pitfall traps and soil samples. A total of 2175 spiders, 78 species in 18 families, were recovered in Kenya and 284 spiders, 34 species in nine families, were recovered in South Africa. Lycosidae was the most abundant family, accounting for >50% of all individual spiders and 27.6% by species richness. Spiders were significantly more abundant at the Kenyan sites than in South Africa while species diversity was significantly higher in South Africa than at the Kenyan sites. At all sites, spider abundance was significantly higher in the ‘push–pull’ than in the maize monocrop plots. However, the overall spider diversity was only significantly higher in the ‘push–pull’ than in the maize monocrop plots in South Africa. Moreover, species dominance did not differ between the two cropping systems at all sites. The results showed that the ‘push–pull’ system evidently enhances overall abundance of spiders, illustrating its potential in further pest control in the maize agroecosystems where spiders may often be one of the most important predatory groups.     

Phospholipid, galactolipid and free sterol composition of fibrous roots from citrus genotypes differing in chloride exclusion ability

Abstract Fibrous roots of four citrus hybrids and parent rootstocks from which the hybrids were generated, all selected for their different Cl^? exclusion abilities, were assayed for phospholipid, galactolipid and free 4-desmethylsterol content. There was no correlation between a plant's ability to exclude Cl^? and the level of either phospholipid, galactolipid, or total free sterol in the roots of control plants. However, an inverse correlation was established between the ratio of phospholipid to free sterol in control roots and total leaf Cl^? levels of plants treated with 50 mol m^?3 NaCl for 56 d. With the exception of a significant decrease in hybrid 80-05-05, galactolipid levels were unaffected by salt treatment. Phospholipid levels were significantly increased in two parent rootstocks viz. Trifoliate orange (Poncirus trifoliata (L.). Raf.) and Carrizo citrange (Citrus sinensis (L.) Osbeck ×P. trifoliata) and one hybrid (80-02-08) but were otherwise unchanged by salt treatment. Free sterol levels were significantly increased by salt treatment in all of the better Cl^? excluders except Carrizo citrange i.e. in Rangpur lime (Citrus reticulata Blanco var. austera hybrid?), Cleopatra mandarin (Citrus reticulata Blanco) and all hybrids except 80–05–13. In all genotypes examined, salt-treatment resulted in a significant decrease in the ratio of sitosterol to stigmasterol reflecting, primarily, an increase in the stigmasterol level. The two poorer Cl^? excluders (Trifoliate orange and hybrid 80–05–13) both underwent a significant decrease in the ratio of ‘more planar’ to ‘less planar’ sterols. The inverse correlation between the phospholipid to free sterol ratio of control plants and leaf Cl^? level of salt treated plants suggests that this ratio has the potential to be used as a biochemical marker of Cl^? exclusion ability in citrus.     

Re-Examining the Performance of MRP and Kanban Material Control Strategies for Multi-Product Flexible Manufacturing Systems

Material control schemes can be classified as push, pull, or hybrid strategies. This article compares the performance of MRP (push) and kanban (pull) for a multi-stage, multi-product manufacturing system. Using simulation experiments we analyze system performance under different product mixes and observe that in certain environments with advance demand information kanban-based pull strategies can lead to significant inefficiencies. In these environments MRP-type push strategies yield better performance in terms of inventories and service levels. We also study the impact of design parameters such as safety lead time and safety stock policies on system performance and observe that for low and medium values of system loads, safety lead time policies yield better system performance than safety stock policies. These insights can be helpful in designing efficient MRP-type push strategies in multi-product environments.     

Conformational studies of parathyroid hormone (PTH)/PTH‐related protein (PTHrP) point‐mutated hybrids

The N‐terminal 1–34 segments of both parathyroid hormone (PTH) and parathyroid hormone‐related protein (PTHrP) bind and activate the same membrane receptor in spite of major differences between the two hormones in their amino acid sequence. Recently, it was shown that in (1–34)PTH/PTHrP segmental hybrid peptides, the N‐terminal 1–14 segment of PTHrP is incompatible with the C‐terminal 15–34 region of PTH leading to substantial reduction in potency. The sites of incompatibility were identified as positions 5 in PTH and 19 in PTHrP. In the present paper we describe the synthesis, biological evaluation, and conformational characterization of two point‐mutated PTH/PTHrP 1–34 hybrids in which the arginine residues at positions 19 and 21 of the native sequence of PTHrP have been replaced by valine (hybrid V²¹) and glutamic acid (hybrid E¹⁹), respectively, taken from the PTH sequence. Hybrid V²¹ exhibits both high receptor affinity and biological potency, while hybrid E¹⁹ binds weakly and is poorly active. The conformational properties of the two hybrids were studied in aqueous solution containing dodecylphosphocholine (DPC) micelles and in water/2,2,2‐trifluoroethanol (TFE) mixtures. Upon addition of TFE or DPC micelles to the aqueous solution, both hybrids undergo a coil‐helix transition. The maximum helix content in 1 : 1 water/TFE, obtained by CD data for both hybrids, is ∼ 80%. In the presence of DPC micelles, the maximum helix content is ∼ 40%. The conformational properties of the two hybrids in the micellar system were further investigated by combined 2D‐nmr, distance geometry (DG), and molecular dynamics (MD) calculations. The common structural motif, consisting of two helical segments located at N‐ and C‐termini, was observed in both hybrids. However, the biologically potent hybrid V²¹ exhibits two flexible sites, centered at residues 12 and 19 and connecting helical segments, while the flexibility sites in the weakly active hybrid E¹⁹ are located at position 11 and in the sequence 20–26. Our findings support the hypothesis that the presence and location of flexibility points between helical segments are essential for enabling the active analogs to fold into the bioactive conformation upon interaction with the receptor. © 1999 John Wiley & Sons, Inc. Biopoly 50: 525–535, 1999     

Analysis of myogenesis by somatic cell hybridization. II. Retention of myogenic competence and suppression of transformed properties in hybrids between differentiation competent and incompetent rat L6 myoblasts

This study describes the characteristics of hybrids between two closely related rat myoblast lines, which differ both in the ability to express their program of differentiation and in the expression of neoplastic properties. Myogenic, nonneoplastic L6J1-S cells were hybridized with nonmyogenic, neoplastic L6J1-N1 cells. Six hybrid clones were isolated and expanded for analysis of myogenic competence, and four of these clones were also evaluated for parameters of transformation, including tumorigenicity, ability to clone in agar, and surface fibronectin. In addition to our analysis of isolated clones, we also assessed myogenic differentiation in colonies representing 226 early hybrid clones. Results of all these analyses demonstrate that the myogenic phenotype is retained and that the tumorigenic/transformed phenotype is suppressed in the hybrids. Furthermore, our results indicate that when the programs for myogenesis and neoplastic transformation are confronted within a single cell, they are expressed as mutually exclusive alternatives. In contrast to these results on myogenic X nonmyogenic L6 hybrids, it has been reported that isolated clones of A9 X L6 exhibited extinction of myogenic competence and retention of transformed properties. We have evaluated myotube formation in over 300 early hybrid clones between A9 and either diploid or subtetraploid L8 rat myoblasts. Our results demonstrate that all of these hybrid clones exhibit extinction regardless of the ploidy of the myoblast parent, and they further indicate that extinction is not a consequence of chromosome loss. These results support the conclusion that in A9 X L6 hybrids, the nonmyogenic, transformed phenotype is dominant.     

Highly solvatochromic fluorescent naphthalimides: Design,synthesis, photophysical properties and fluorescence switch-on sensing of ct-DNA

We report the design, synthesis and photophysical properties of highly solvatochromic donor/acceptor substituted naphthalimide based fluorophores. The synthesized naphthalimides containing propargyl ends showed highly solvatochromic intramolecular charge transfer (ICT) feature as was revealed from the UV–visible, fluorescence photophysical properties of these fluorophores and DFT/TDDFT calculation. Fluorescence life times for the imide fluorophores were also measured in different solvents. The solid state photophysical property of donor substituted naphthalimide 1 showed promising for future application in material sciences. Furthermore, both the donor/acceptor substituted naphthalimide fluorophores 1–2 were exploited in sensing calf-thymus DNA via switch-on fluorescence response. The propargyl linker containing naphthalimides can further be exploited for the synthesis of labeled biomolecular building blocks.     

Molecular docking of novel donor–π–acceptor dicyanomethylenedihydrofuran-based fluorescent chromophores

A series of donor–π–acceptor dicyanomethylenedihydrofuran (DCDHF)-based chromophores comprising different π-aryl bridges and different terminal groups was synthesized and characterized. The chromophores were synthesized via Knoevenagel condensation of the active methyl-bearing DCDHF (electron acceptor) with a tertiary amine-containing arylaldehyde (electron donor) in dry pyridine at room temperature in the presence of a few drops of acetic acid. The synthesis approach involved the development of phenyl(thienyl)vinyl-bridged dicyanomethylenedihydrofuran dyes with a tertiary amine terminal group. Both absorption and emission spectra were explored. The strong emission properties detected using the synthesized chromophores could be attributed to intramolecular charge transfer. The chemical structures of the synthesized chromophores were verified using ¹H/¹³C nuclear magnetic resonance and Fourier transform infrared spectroscopy. Both tertiary amine-containing and arylaldehyde groups were found to influence the biological properties of the synthesized chromophores. The synthesized (DCDHF)-based hybrids were tested to examine antibacterial effectiveness. Derivatives 1 and 2 demonstrated activity towards Gram-positive bacteria rather than Gram-negative bacteria when compared with an amoxicillin antibiotic reference. Finally, molecular docking inspiration was undertaken to determine their binding relationships (PDB code: 1LNZ).     

Design,Synthesis, and Biological Evaluation of Novel Amyl Ester Tethered Dihydroartemisinin-Isatin Hybrids as Potent Anti-Breast Cancer Agents

A series of novel amyl ester tethered dihydroartemisinin-isatin hybrids 4a–d and 5a–h were designed, synthesized, and evaluated as anti-breast cancer agents. The synthesized hybrids were preliminarily screened against estrogen receptor-positive (MCF-7 and MCF-7/ADR) and triple-negative (MDA-MB-231 and) breast cancer cell lines. Three hybrids 4a , d and 5e not only were more potent than artemisinin and adriamycin against drug-resistant MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines, but also displayed non-cytotoxicity towards normal MCF-10 A breast cells, and the SI values were >4.15, indicating their excellent selectivity and safety profiles. Thus, hybrids 4a , d and 5e could act as potential anti-breast cancer candidates and were worthy of further preclinical evaluations. Moreover, the structure–activity relationships which may facilitate further rational design of more effective candidates were also enriched.