Design,synthesis, docking,and anticancer evaluations of phthalazines as VEGFR-2 inhibitors

Twenty new N-substituted-4-phenylphthalazin-1-amine derivatives were designed, synthesized, and evaluated for their anticancer activities against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 7f was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, with 50% inhibition concentration, IC₅₀ = 3.97, 4.83, and 4.58 µM, respectively, which is more potent than both sorafenib (IC₅₀ = 9.18, 5.47, and 7.26 µM, respectively) and doxorubicin (IC₅₀ = 7.94, 8.07, and 6.75 µM, respectively). Fifteen of the synthesized derivatives were selected to evaluate their inhibitory activities against VEGFR-2. Compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.08 µM, which is more potent than sorafenib (IC₅₀ = 0.10 µM). Compound 8c inhibited VEGFR-2 at an IC₅₀ value of 0.10 µM, which is equipotent to sorafenib. Moreover, compound 7a showed very good activity with IC₅₀ values of 0.11 µM, which is nearly equipotent to sorafenib. In addition, compounds 7d , 7c , and 7g possessed very good VEGFR-2-inhibitory activity, with IC₅₀ values of 0.14, 0.17, and 0.23 µM, respectively.     

Design,synthesis, and antitumor evaluation of quinoline‐imidazole derivatives

A series of compounds bearing quinoline‐imidazole ( 8a–e , 9a–e , 10a–e , 11a–e , and 12a–e ) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC‐3, HepG2, and MCF‐7 cells by the MTT method, with NVP‐BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC‐3 cells, with half‐maximal inhibitory concentration (IC₅₀) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP‐BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC₅₀ value of 12a against the cell line WI‐38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K‐Akt‐mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP‐BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C‐6 of the quinoline ring was replaced by a bromine atom.

     

Design,synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, ¹H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC₅₀ values (0.25–1.7 µM) were lower than that of indomethacin (IC₅₀ = 9.47 µM) and somewhat higher than that of celecoxib (IC₅₀ = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC₅₀ values of 0.02–74.03 µM, while the IC₅₀ of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

     

The application of tandem aza-wittig reaction to synthesize artemisinin-guanidine hybrids and their anti-tumor activity

Three series of novel artemisinin–guanidine hybrids 4a–4f , 8a–8h and 9a–9h have been facilely synthesized via four‐component reaction (aza‐Wittig reaction) and evaluated for their anti‐tumor activities against A549, HT‐29 and MDA‐MB‐231 cell lines in vitro. All of the tested compounds showed enhanced anti‐tumor activities with IC₅₀ values ranging from 0.02 µM to 12.0 µM as compared to DHA (dihydroartemisinin). Among them, artemisinin derived dimers, compounds 9b (IC₅₀ = 0.05 µM), 9d (IC₅₀ = 0.06 µM) and 9f (IC₅₀ = 0.02 µM) were found to be most active against HT29 cells.     

Design,synthesis, molecular docking,and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors

Novel series of benzoxazole s 4 _a‐f ‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 _e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC₅₀ = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 _c , 5 _f , 6 _b , 5 _d , and 6 _c showed the highest anticancer activities against HepG2 cells with IC₅₀ of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC₅₀ of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC₅₀ of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC₅₀ of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 _c‐f and 6 _b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5 _e and 5 _c potently inhibited VEGFR‐2 at lower IC₅₀ values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC₅₀ = 0.1 ± 0.02 µM). Compound 5 _f potently inhibited VEGFR‐2 at low IC₅₀ value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of benzoxazole/benzothiazole derivatives 4a–c – 11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f , and 9c showed the highest anticancer activities against HepG2 cells with IC₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC₅₀ values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h , and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Design,synthesis, and biological evaluation of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as potential multitarget anticancer agents

A series of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as insulin‐like growth factor 1 receptor (IGF‐1R) inhibitors was designed and synthesized. IGF‐1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU‐DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR‐1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC₅₀] values, HepG2: 2.98 ± 1.11 μM and WSU‐DLCL2: 4.34 ± 0.84 μM) exhibited good inhibitory activities against fibroblast growth factor receptor‐2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC₅₀ values ranging from 2.14 to 12.20 μM. Additionally, the cell‐cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.     

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

A new series of N-substituted pyrazoline derivatives 6a–g , 7a–g , 8a–g , and 9a–g was synthetized by reaction of hydrazine derivatives and chalcone–thiazole hybrids bearing nitrogen mustard 5a–g . The chalcones 5a–g were obtained by Claisen–Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a–g . These new compounds 6/7/8/9a–g were screened for their antifungal activity against Cryptococcus neoformans, with IC₅₀ values of 3.9–7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e – g . Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl ( 6a,b ) and N-formyl pyrazolines ( 7a , 7b , 7c , and 7g ) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g , 8f , and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC₅₀ values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.     

5-(4-Methoxybenzylidene)thiazolidine-2,4-dione-derived VEGFR-2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione derivatives, 5a–g and 7a–f , was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF-7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f , 7e , 7d , and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF-7 cancer cell lines. Compound 7f (IC₅₀ = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively) exhibited a higher activity than sorafenib (IC₅₀ = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 µM, respectively) against HepG2 and MCF-7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively) against HepG2 and MCF-7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a–g and 7a–f , were evaluated for their inhibitory activities against vascular endothelial growth factor receptor-2 (VEGFR-2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.12 ± 0.02 µM, which is nearly the same as that of sorafenib (IC₅₀ = 0.10 ± 0.02 µM). Compounds 7e , 7d , 7c , and 7b exhibited the highest activity, with IC₅₀ values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 µM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR-2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.     

Induction of apoptosis through tubulin inhibition in human cancer cells by new chromene-based chalcones

Context: As microtubules are highly involved in cellular growth, it appears to be a preferential target for cancer treatment. Therefore, many efforts have been performed to discover drugs that affect on microtubule function. Several microtubule inhibitors are in various stages of laboratory evaluations and clinical trials.

Objective: A series of chromene-based chalcones with chlorine, methoxy, fluorine, tetrahydropyranyloxy and cyanide substituents were prepared and evaluated for cytotoxic effects against K562 and SK-N-MC cell lines, and the inhibitory effect on tubulin polymerization was studied as well.

Materials and methods: MTT, tubulin polymerization assays and binding measurements were evaluated by using related spectroscopy. Immunocytochemical study, morphological observations and apoptosis assay were examined using a fluorescence microscope and a flow cytometer.

Results: (E)-3-(6-Chloro-2H-chromen-3-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one (compound 14) proved to be the most active in this series as an inhibitor of tubulin assembly [IC₅₀, 19.6 µM] and cytotoxic agent on K562 cells [IC₅₀, 38.7 µM]. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization and reduced the in vitro assembly and bundling of proto-filaments. Also, compound 14 bound to the tubulin with a dissociation constant of 9.4 ± 0.7 µM and induced conformational changes in this protein.

Discussion and conclusion: This study suggests that the compound 14 could be a good antitumor agent because of its biological functions. Compound 14 appears to bind directly to tubulin and thereby perturbs microtubule stability and the function of the spindle apparatus, which causes cancer cells to arrest and undergo apoptosis.     

Synthesis and cytotoxic evaluation of some new phthalazinylpiperazine derivatives

A new series of 1,4‐disubstituted phthalazinylpiperazine derivatives 7a–f , 12a–f and 20a–f were designed and synthesized in order to develop potent and selective antitumor agents. The target compounds were screened for their cytotoxic activities against A549, HT‐29 and MDA‐MB‐231 cancer cell lines in vitro. Among them, compounds 7a–f exhibited excellent selectivity for MDA‐MB‐231 with IC₅₀ values ranging from 0.013 µM to 0.079 µM. The most promising compound, 7e (IC₅₀ = 2.19 µM, 2.19 µM, 0.013 µM), was 9.3, 10, and 4.9 × 10³ times more active than vatalanib (IC₅₀ = 20.27 µM, 21.96 µM, 63.90 µM), respectively.     

Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G‐2, Hep‐2, and Caco‐2). Compounds 18b, 19b, 23, 25b , and 26 showed strong potencies against all tested cell lines with IC₅₀ values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC₅₀ values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC₅₀ = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC₅₀ value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell‐cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G‐2 cells. It has revealed cell‐cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl‐2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.     

Design,synthesis, molecular docking,and anticancer evaluations of 1-benzylquinazoline-2,4(1H,3H)-dione bearing different moieties as VEGFR-2 inhibitors

A novel series of 1-benzylquinazoline-2,4(1H,3H)-dione derivatives, 6a , b to 11a – e , was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT-116, and MCF-7 cells. Compounds 11b , 11e , and 11c were found to be the most potent derivatives of all tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with GI₅₀ = 9.16 ± 0.8, 5.69 ± 0.4, 5.27 ± 0.2 µM, 9.32 ± 0.9, 6.37 ± 0.7, 5.67 ± 0.5 µM, and 9.39 ± 0.5, 6.87 ± 0.7, 5.80 ± 0.4 µM, respectively. These compounds exhibited nearly the same activity as sorafenib against HepG2 and HCT-116 cells and a higher activity against MCF-7 cells (GI₅₀ = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). Also, these compounds displayed a lower activity than doxorubicin against HepG2 cells and a higher activity against HCT-116 and MCF-7 cells (GI₅₀ = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). The most active antiproliferative derivatives, 6a , b , 8 , 9 , and 11a – e , were selected to evaluate their enzymatic inhibitory activity against VEGFR-2. Compounds 11b , 11e , and 11c potently inhibited VEGFR-2 at IC₅₀ values of 0.12 ± 0.02, 0.12 ± 0.02, and 0.13 ± 0.02 µM, respectively, which are nearly equipotent as sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.     

3′-Methyl-4-thio-1H-tetrahydropyranspiro-5′-hydantoin platinum complex as a novel potent anticancer agent and xanthine oxidase inhibitor

In this study, a Pt(IV) complex with 3′-methyl-4-thio-1H-tetrahydropyranspiro-5′-hydantoin (complex 1 ) was synthesized. The structure was determined via elemental analyses, infrared, ¹H, and ¹³C nuclear magnetic resonance techniques. Density functional theory calculations were applied to optimize the molecular geometry and to calculate structural parameters and vibrational frequencies. The cytotoxicity of the newly synthesized complex 1 was assessed against K-562 and REH cells and compared with the cytotoxic effects of the ligand ( L ) and its Pd(IV) complex (complex 2 ). Complex 1 exhibited a better cytotoxic activity (IC₅₀ = 76.9 µM against K-562 and 15.6 µM against REH cells) than L and complex 2 , which was closer to the cytotoxic effect of cisplatin (IC₅₀ = 36.9 μM and 1.07 μM against K-562 and REH cells, respectively), as compared with the ligand and complex 2 . L and its complexes 1 and 2 were evaluated for inhibitory activity against xanthine oxidase (XO) in vitro, as compared with allopurinol (IC₅₀ = 1.70 μM). Complex 1 was shown as a potent XO inhibitor, with an IC₅₀ value of 19.33 μM, and the binding mode with the enzyme was predicted by molecular docking. Its inhibitory activity against XO is a potential advantage that might result in improved profile and anticancer activity.     

Synthesis and Evaluation of Benzophenone O‐Glycosides as α‐Glucosidase Inhibitors

The first total synthesis of benzophenone O‐glycosides (iriflophenone 2‐O‐α‐L ‐rhamnopyranoside: 1 and aquilarisinin: 2 ) isolated from the leaves of Aquilaria sinensis and related new derivatives ( 3 – 12 ) was accomplished through suitable protecting group manipulations and glycosylation starting from commercially available L ‐rhamnose, D ‐glucose, D ‐galactose, D ‐mannose, D ‐xylose, and 1,3,5‐trihydroxybenzene. All synthesized benzophenone O‐glycosides were evaluated for their inhibitory activities against α‐glucosidase. Of these, benzophenone O‐glycosides 4 and 10 exhibited the most potent inhibitory activity in vitro against α‐glucosidase with IC₅₀ values of 168.7 ± 13.9 and 210.1 ± 23.9 µM, respectively, when compared with that of the positive control acarbose with an IC₅₀ value of 569.3 ± 49.7 µM.     

Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC₅₀ 3.0 µM) and 8f (IC₅₀ 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC₅₀ 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC₅₀ 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Quinones and coumarins from Ajania salicifolia and their radical scavenging and cytotoxic activity

Abstract

1,4-Naphthoquinone (1) and a new coumarin (3) were isolated from Ajania salicifolia, together with two known compounds (2, 4). The structures and stereochemistry of new compounds were elucidated using spectroscopic methods. Two compounds exhibited potent ABTS cation radical scavenging activities with IC₅₀ values ranging 7.97–8.44 μM. Two quinones (1, 2) exhibited moderate cytotoxic activity against the human cancer cell lines (Hela, HepG2, and K562) with IC₅₀ values of 11.24–35.15 μM in vitro. This is the first report of naphthoquinone in the genus Ajania.     

Efficient Total Synthesis and Biological Activities of 6‐Deoxyisojacareubin

6‐Deoxyisojacareubin was directly synthesized in a six‐step route with an overall yield of about 20%. In this route, the excellent site selectivity of this Claisen rearrangement‐cyclization reaction cascade was achieved by inserting a bulky p‐tosyl group into the free 1‐OH, and in the last step, some efficient demethylation methods were explored. Furthermore, all synthesized intermediates including 6‐deoxyisojacareubin were evaluated for their inhibitory activity against the QGY‐7703 cell line. Of these, compound 1 and 6‐deoxyisojacareubin showed moderate activities with IC₅₀ values of 39.61 and 9.65 µM, respectively, when compared to the positive control 5‐fluorouracil with an IC₅₀ value of 11.24 µM. Further investigation using non‐radioactive detection of protein kinase C (PKC) suggested that these two compounds possessed potency in the inhibition of PKC.     

Dillapiole as Antileishmanial Agent: Discovery,Cytotoxic Activity and Preliminary SAR Studies of Dillapiole Analogues

In this paper, the isolation of dillapiole ( 1 ) from Piper aduncum was reported as well as the semi‐synthesis of two phenylpropanoid derivatives [di‐hydrodillapiole ( 2 ), isodillapiole ( 3 )], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure–activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC₅₀ = 69.3 µM) and Leishmania brasiliensis (IC₅₀ = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC₅₀ = 99.9 µM for L. amazonensis and IC₅₀ = 90.5 µM for L. braziliensis) and 3 (IC₅₀ = 122.9 µM for L. amazonensis and IC₅₀ = 109.8 µM for L. brasiliensis) were less active than dillapiole ( 1 ). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.