Design,Synthesis, Cytotoxic Screening and Molecular Docking Studies of Novel Hybrid Thiosemicarbazone Derivatives as Anticancer Agents

Thiosemicarbazones have been the focus of scientists owing to their broad clinical anticancer range. Herein, A Series of new thiosemicarbazone derivatives 5 – 9 were synthesized and confirmed through the use of different spectroscopic techniques along with elemental analysis. The in vitro cytotoxic activity of compounds 5 – 9 against MCF-7 and A549 cell lines and normal breast cells were assessed. Several compounds were found to be active. The most active compound 7 caused MCF-7 cell cycle arrest at G1/ S phases; and induced apoptosis at the pre-G1 phase. The apoptosis-inducing activity of compound 7 was proofed by the elevation of caspase 3/7 activity and also by up-regulation of the expression of Bax and p53 proteins together with the down-regulation of the expression of the Bcl-2 protein. It also had a strong inhibitory effect topoisomerase IIβ enzyme. Molecular Docking study revealed that the synthesized compounds had good docking scores compared to the standard drug Etoposide towards the topoisomerase IIβ protein (3QX3). Overall, these findings confirmed that the new thiosemicarbazone derivatives could aid in the development of promising cancer drug candidates.     

Design and Synthesis of Novel Thiazolo[5,4‐d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR‐2 has been demonstrated as a key method against tumor‐associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4‐d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(3,4‐dimethylphenyl)urea) and 3m (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(4‐methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC₅₀=1.65 and 3.52 μm , respectively). Compound 3l also showed the best potency against VEGFR‐2 at 50 μm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.     

Synthesis,Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2‐(2‐hydroxyphenyl)‐4H‐benzo[e][1,3]oxazin‐4‐one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC₅₀ values of 1.268 and 3.254 μm , respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors     

Synthesis,Biological Activity and Action Mechanism Study of Novel Chalcone Derivatives Containing Malonate

A series of novel chalcone malonate derivatives were synthesized and their antibacterial and antiviral activities were evaluated. All target compounds were characterized by spectral data. The results of antimicrobial bioassay showed that one compound (diethyl [3‐(naphthalen‐2‐yl)‐1‐(3‐nitrophenyl)‐3‐oxopropyl]propanedioate) showed excellent antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC₅₀ value of 10.2 μg/mL, which is significantly superior to bismerthiazol (71.7 μg/mL) and thiodiazole copper (97.8 μg/mL). At the same time, the mechanism of two compounds was confirmed by scanning electron microscopy. In addition, another compound (diethyl [3‐(naphthalen‐2‐yl)‐1‐(4‐nitrophenyl)‐3‐oxopropyl]propanedioate) showed significant curative activity to tobacco mosaic virus, with a value of 74.3 %, which was superior to 53.3 % of ningnanmycin. The results of microscale thermophoresis also showed that the Kd value of the combination of two compounds with the coat protein of tobacco mosaic virus was 0.211 and 0.166 μmol/L, which was better than 0.596 μmol/L of ningnanmycin. At the same time, the molecular docking of two compounds with tobacco mosaic virus‐coat protein shows that the compound is well embedded in the pocket between the two subunits of tobacco mosaic virus‐coat protein. These results show that chalcone derivatives containing malonate group can be considered as activators in the design of antibacterial and antiviral agents.     

Synthesis and Characterization of Novel Thiazolo[3,2‐a]pyrimidine Derivatives and Evaluation of Antioxidant and Cytotoxic Activities

A series of novel thiazolo[3,2‐a]pyrimidines were synthesized and characterized by FT‐IR, ¹H, ¹³C‐NMR and mass techniques. Their antioxidant activities were investigated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging assay and the results showed that all the synthesized compounds exhibit good antioxidant activity. In addition, it was found that any substituent on the aromatic ring of the products plays an important role in their antioxidant activity. In vitro cytotoxicity of compounds 4a – 4j was investigated using MTT cell viability assay. Among these compounds, 6‐ethyl 2,3‐dimethyl 5‐(4‐chlorophenyl)‐7‐methyl‐2,3‐dihydro‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐2,3,6‐tricarboxylate ( 4e ) bearing a chlorine substituent displayed the highest cytotoxic effect (IC₅₀=6.26±0.6 μm ) in comparison with doxorubicin (IC₅₀=0.68±0.1 μm ) as a standard after 72 h. Therefore, it is assumed that these compounds could be used as effective antioxidant and cytotoxic agents.     

Synthesis,Antiproliferative Evaluation,and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused Thiazole-Amide Derivatives

Twenty novel longifolene-derived tetraline fused thiazole-amide compounds were synthesized from longifolene, a renewable natural resource. Their structures were characterized by FT-IR, NMR, ESI-MS, and elemental analysis. The in vitro antiproliferative activity of these compounds against SK-OV-3 ovarian cancer cell lines, MCF-7 human breast cancer cell lines, HepG2 human liver cancer cell lines, A549 human lung adenocarcinoma cell lines, and T-24 human bladder cancer cell lines was tested by MTT assay. Compounds 6a – 6c displayed significant and broad-spectrum antiproliferative activity against almost the tested cancer cell lines with IC₅₀ in the range of 7.84 to 55.88 μM, of which compound 6c exhibited excellent antiproliferative activities with 7.84 μM IC₅₀ against SKOV-3, 13.68 μM IC₅₀ against HepG2, 15.69 μM IC₅₀ against A549, 19.13 μM IC₅₀ against MCF-7, and 22.05 μM IC₅₀ against T-24, showing better and broad-spectrum antiproliferative effect than that of the positive control 5-FU. Furthermore, the action model was analyzed by the molecular docking study. Some intriguing structure-activity relationships were found and discussed herein by DFT theoretical calculation.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Synthesis and Antimicrobial Evaluation of Novel Chiral 2‐Amino‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine Derivatives

New N‐substituted‐2‐amino‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine derivatives were synthesized employing a convenient one‐pot three‐component method and their structures were characterized by ¹H‐NMR and single crystal X‐ray diffraction analysis. All the synthesized compounds were in vitro screened for antimicrobial activity against Gram‐positive (Sarcina lutea) and Gram‐negative bacteria (Escherichia coli). In this work, we introduced a chiral residue on the tetrahydropyridine nitrogen, the hitherto the less investigated position on this pharmacophore in order to explore the effect. The antibacterial results showed that the synthesized compounds were active only against Gram‐positive bacteria and the (R)‐enantiomers displayed a greater antimicrobial potency than their (S)‐counterparts. The structure–activity relationship here investigated may provide some interesting clues for future development of tetrahydrothienopyridine derivatives with higher antimicrobial activity.     

Synthesis and Evaluation of Water‐Soluble 2‐Aryl‐1‐Sulfonylpyrrolidine Derivatives as Bacterial Biofilm Formation Inhibitors

The approach to the novel 1‐[(2‐aminoethyl)sulfonyl]‐2‐arylpyrrolidines via unique intramolecular cyclization/aza‐Michael reactions of N‐(4,4‐diethoxybutyl)ethenesulfonamide have been developed, which benefits from high yields of target compounds, mild reaction conditions, usage of inexpensive and low‐toxic reagents, and allows for wide variability in both amine and aryl moieties. Biotesting with whole‐cell luminescent bacterial biosensors responding to DNA damage showed that all tested compounds are not genotoxic. Tested compounds differently affect the formation of biofilms by Vibrio aquamarinus DSM 26054. Some of the tested compounds were found to suppress the bacterial biofilms growth and thus are promising candidates for further studies.     

Hybrid Pharmacophore Design,Molecular Docking,Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

A series of hybrid aldimine‐type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4‐triazole‐3‐thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4‐nitro, 2‐nitro, 3‐nitro, 4‐Cl‐3‐nitro, and 4‐Me₂N) on the aldehyde ring were the best compounds with remarkable binding energies (?9.09, ?9.07, ?8.63, ?8.11, and ?8.07 kcal mol^?1, respectively) compared to colchicine (?8.12 kcal mol^?1). These compounds were also showed remarkable binding energies from ?10.66 to ?9.79 and ?10.12 to ?8.95 kcal mol^?1 on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF‐7, and A549 cancer cell lines indicated that 4‐nitro and 2‐nitro substituted compounds were the most effective agents by mean IC₅₀ values of 11.84 ± 1.01 and 19.92 ± 1.36 μm , respectively. 4‐Nitro substituted compound (5 μm ) and 2‐nitro substituted compound (30 μm ) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm ) and 4‐nitro substituted compound displayed IC₅₀ values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm ). This compound also showed the lowest MIC values on all tested microbial strains including three Gram‐positive, four Gram‐negative, and three yeast pathogens.     

Synthesis and Biological Activity of New 4‐tert‐Butylcyclohexanone Derivatives

In the synthesis performed in this study, derivatives of 4‐tert‐butylcyclohexanone 1 were obtained using typical reactions of organic synthesis. The bioactivity of the selected compounds was evaluated. 1‐(Bromomethyl)‐8‐tert‐butyl‐2‐oxaspiro[4.5]decan‐3‐one ( 5 ) was characterized by attractant properties against larvae and a weak feeding deterrent activity against adults of Alphitobius diaperinus Panzer . This bromolactone was a moderate antifeedant towards Myzus persicae Sulzer . In addition, ethyl (4‐tert‐butylcyclohexylidene)acetate ( 2 ) and bromolactone 5 displayed antibacterial activity. The strongest bacteriostatic effect was observed against Gram‐positive strains: Bacillus subtilis and Staphylococcus aureus. The bromolactone 5 also limited the growth of Escherichia coli strain.     

新型2-喹诺酮类Polo样激酶1抑制剂的设计合成及分子对接研究

目的:设计合成新型2-喹诺酮类Polo样激酶1(Plk1)抑制剂。方法:以Plk1抑制剂ON 01910为先导化合物,利用生物电子等排原理设计一系列2-喹诺酮类衍生物,用Autodock软件将该类化合物与Plk1进行分子对接和虚拟筛选,计算结合自由能;以取代的氯(溴)苄为起始原料,先后经巯基乙酸取代、双氧水氧化、与(对甲氧基)苯胺酰化,再经环合、水解制得目标化合物。结果:设计的化合物大多数与Plk1的结合自由能均比ON 01910的低,结合强度高、稳定性好;合成了16个2-喹诺酮类衍生物,产物结构经1H-NMR确证。结论:所得化合物中有15个为新化合物,化合物的结构设计科学合理,虚拟筛选结果良好,为后续实体筛选和化合物结构优化提供了理论依据和参考。     

Design,Synthesis, and Cytotoxic Activity of 3‐Aryl‐N‐hydroxy‐2‐(sulfonamido)propanamides in HepG2, HT‐1080, KB,and MCF‐7 Cells

A new series of (sulfonamido)propanamides ( 6a1 – 6a13 , 6b1 – 6b15 , 7c1 – 7c5 , 6d1 – 6d5 , 6e1 – 6e6 ) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their in vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT‐1080), mouth epidermal carcinoma (KB), and breast adenocarcinoma (MCF‐7) cell lines with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls. Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most potent compound, 6a7 , shows the IC₅₀ values of 29.78±0.516 μm , 30.70±0.61 μm , and 64.89±3.09 μm in HepG2, HT‐1080, KB, and MCF‐7 cell lines, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.     

Novel Nociceptin Analogues: Synthesis and Biological Activity

Syntheses are described of the nociceptin (1–13) amide [NC(1–13)-NH₂] and of several analogues in which either one or both the phenylalanine residues (positions 1 and 4), the arginine residues (positions 8 and 12) and the alanine residues (positions 7 and 11) have been replaced by N-benzyl-glycine, N-(3-guanidino-propyl)-glycine and β-alanine, respectively. The preparation is also described of NC(1–13)-NH₂ analogues in which either galactose or N-acetyl-galactosamine are β-O-glycosidically linked to Thr⁵ and/or to Ser¹⁰. Preliminary pharmacological experiments on mouse vas deferens preparations showed that Phe⁴, Thr⁵, Ala⁷ and Arg⁸ are crucial residues for OP₄ receptor activation. Manipulation of Phe¹ yielded peptides endowed with antagonist activity but [Nphe¹] NC(1–13)-NH₂ acted as an antagonist still possessing weak agonist activity. Introduction of the βAla residue either in position 7 or 11 of the [Nphe¹] NC(1–13)-NH₂ sequence, abolished any residual agonist activity and [Nphe¹, βAla⁷] NC(1–13)-NH₂ and [Nphe¹, βAla¹¹] NC(1–13)-NH₂ acted as competitive antagonists only. Modification of both Ala⁷ and Ala¹¹ abolished the antagonist activity of [Nphe¹]NC(1–13)-NH₂ probably by hindering receptor binding. Changes at positions 10 and 11 gave analogues still possessing agonist activity. [Ser(βGal)¹⁰] NC(1–13)-NH₂ displayed an activity comparable with that of NC(1–13)-NH₂, [Ser(βGalNAc)¹⁰] NC(1–13)-NH₂ and [βAla¹¹] NC(1–13)-NH₂ were five and 10 times less active, respectively.The α-amino acid residues are of the l-configuration. Standard abbreviations for amino acid derivatives and peptides are according to the suggestions of the IUPAC-IUB Commission on Biochemical Nomeclature (1984), Eur. J. Biochem. 138, 9–37. Abbreviations listed in the guide published in (2003), J. Peptide Sci. 9, 1–8 are used without explanation.     

Synthesis and Biological Evaluation of Sigma‐1 (σ1) Receptor Ligands Based on Phenyl‐1,2,4‐oxadiazole Derivatives

In this study, a series of phenyl‐1,2,4‐oxadiazole derivatives were synthesized and evaluated for anti‐allodynic activity. Structure–activity relationship studies identified 1‐{4‐[3‐(2,4‐dichlorophenyl)‐1,2,4‐oxadiazol‐5‐yl]butyl}piperidine ( 39 ) with excellent affinity for the σ₁ receptor and selectivity for the σ₂ receptor, with poor activity to other central nervous system neurotransmitter receptors and transporters associated with pain. Compound 39 exhibited dose‐dependent efficacy in suppressing the formalin‐induced flinching and attenuating mechanical allodynia in chronic constriction injury‐induced neuropathic rats. These results suggest that compound 39 exerts potent antihyperalgesic activity and could be considered as a promising candidate for treating neuropathic pain.     

Synthesis,Antimicrobial Activities,and Molecular Docking Studies of Dihydrotriazine Derivatives Bearing a Quinoline Moiety

In this article, three series of dihydrotriazine derivatives bearing a quinoline moiety ( 5a , 5b , 8a – 8c , and 9a – 9m ) have been designed, synthesized, and evaluated as antibacterial agents. Compounds 8a – 8c were found to be the most potent of all of the compounds tested with an MIC value of 1 μg/mL against several Gram‐positive (S. aureus 4220 and MRSA CCARM 3506) and Gram‐negative (E. coli 1924) strains of bacteria. In addition, 3‐[4‐amino‐6‐(phenethylamino)‐2,5‐dihydro‐1,3,5‐triazin‐2‐yl)‐6‐[(3‐chlorobenzyl)oxy]quinolin‐2‐ol ( 8a ) showed potent inhibitory activity (MIC=2 μg/mL) against Pseudomonas aeruginosa 2742, indicating that its antibacterial spectrum is similar to those of the positive controls gatifloxacin and moxifloxacin. Structure‐activity relationships (SAR) analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency of the quinoline compounds. In vitro enzyme study implied that compound 8a also displayed DHFR inhibition.     

Design,Microwave‐Assisted Synthesis and in Vitro Antibacterial and Antifungal Activity of 2,5‐Disubstituted Benzimidazole

Seventeen novel 2,5‐disubstituted benzimidazole derivatives were designed, synthesized and evaluated for their antibacterial activities. The tested compounds B1 – B4 and C2 – C6 exhibited not only good antifungal activity but also favorable broad‐spectrum antibacterial activity. Also, the lowest MIC of antibacterial and antifungal activity was 2 μg/mL and 4 μg/mL, respectively. It suggested that the structure of compound including the different substituent and its sites directly affected the efficacy of the synthesized compounds.     

Novel Aminomethyl Derivatives of 4‐Methyl‐2‐prenylphenol: Synthesis and Antioxidant Properties

4‐Methyl‐2‐prenylphenol ( 1 ) was synthesized from para‐cresol and prenol, natural alcohol under the conditions of heterogeneous catalysis. A series of nine new aminomethyl derivatives with secondary and tertiary amino groups were obtained on the basis of compound 1 . A comparative evaluation of their antioxidant properties was carried out using in vitro models. It was established that Mannich base with octylaminomethyl group has radical‐scavenging activity, high Fe²⁺‐chelation ability as well as the ability to inhibit oxidative hemolysis of red blood cells.     

Synthesis,Antiproliferative and Cytotoxic Activities,DNA Binding Features and Molecular Docking Study of Novel Enamine Derivatives

Novel enamine derivatives were synthesized from the reaction of lactone and chalcones and their antiproliferative and cytotoxic activities against six cancer cell lines (e. g., HeLa, HT29, A549, MCF7, PC3 and Hep3B) and one normal cell lines (e. g., FL) were investigated along with their mode of interactions with CT‐DNA. Most of the enamine derivatives with IC₅₀ values of 86–168 μM demonstrated much stronger antiproliferative activity than the starting molecules against the cancer cells. While, among the enamine derivatives, four compounds displayed higher cytotoxic potency than the control drugs (5‐fluorouracil and cisplatin) against the Hep3B cell lines, these compounds did not exhibit any significant toxicity against normal cells, FL. The UV/VIS spectral data suggest that eight compounds cause hypochromism with a slight bathochromic shift (～6 nm), indicating that they bind to the DNA by way of an intercalative or minor groove binding mode. The binding constants of the compounds are in the range of 0.1×103 M^?1–2.3×104 M^?1. The antiproliferative activity of studied enamine derivatives could possibly be due to their DNA binding as well as their cytotoxic properties. In addition to these assays, the chalcones and enamine derivatives were investigated by molecular docking to calculate the synergistic effect of antiproliferative activities against six human cancer cell lines.