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.     

One‐Pot Laccase‐Catalysed Synthesis of 5,6‐Dihydroxylated Benzo[b]furans and Catechol Derivatives,and Their Anticancer Activity

A commercial laccase, Suberase® from Novozymes, was used to catalyse the synthesis of 5,6‐dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI₅₀, TGI and LC₅₀ are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6‐dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI₅₀ = 0.77–9.76 µM), of which two compounds had better activity than the anticancer agent etoposide (GI₅₀ = 0.89 µM). One compound exhibited potent activity (GI₅₀ = 9.73 µM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI₅₀ = 8.79 and 9.30 µM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6‐dihydroxylated benzo[b]furans for their potential application in anticancer therapy.     

Synthesis,Cytotoxicity, and Pro‐Apoptosis Activity of Etodolac Hydrazide Derivatives as Anticancer Agents

Etodolac hydrazide and a novel series of etodolac hydrazide‐hydrazones 3 – 15 and etodolac 4‐thiazolidinones 16 – 26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT‐IR, ¹H NMR, ¹³C NMR, HREI‐MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2‐(1,8‐Diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)acetic acid[(4‐chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC‐3, with 58.24% growth inhibition at 10^?5 M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC‐3 and the rat fibroblast cell line L‐929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC₅₀ value of 54 µM (22.842 µg/mL) against the PC‐3 cells and did not display any cytotoxicity toward the L‐929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase‐3 and Bcl‐2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.     

Synthesis and Biological Evaluation of Novel 6‐Hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐Triazine Derivatives as Potential Antitumor Agents

A series of 6‐hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐triazine derivatives ( 5a – 5l and 8a – 8o ) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for antiproliferative activity against three cancer cell lines (H460, HT‐29, and MDA‐MB‐231). Several potent compounds were further evaluated against two other cell lines (U87MG, H1975). Most of the prepared compounds, particularly compounds 5c and 5j with IC₅₀ values (0.07 and 0.05 µM, respectively) in the nM range, exhibited moderate to excellent antiproliferative activity and high selectivity against the H460 cancer cell line as compared with compound 1 . The most promising compound 5j , possessing a cyano group at the 3‐position of the benzene ring, showed strong antiproliferative activity against H460, HT‐29, and MDA‐MB‐231 cell lines with IC₅₀ values of 0.05, 6.31, and 6.50 µM, which were 4.6‐ to 190.4‐fold more active than compound 1 (9.52, 29.24, and 36.21 µM), respectively.     

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, 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.     

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.

     

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.     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

Synthesis and cytostatic properties of structure-simplified analogs of dolastatin 15*

Abstract: The linear peptide dolastatin 15 ( 1 ), a potent antineoplastic constituent from the shell-less mollusk Dolabella auricularia, has been selected as the lead compound for developing novel antitumor drugs. Recently LU103793 ( 2 ), a synthetic and structure-simplified analog of dolastatin 15, has been demonstrated to be highly cytotoxic [IC₅₀ = 0.1 nm ; M. De Arruda, C.A. Cocchiaro, C.M. Nelson, C. M. Grinnel, B. Janssen, A. Haupt & T. Barlozzari (1995) Cancer Res. 55 , 3085–3092]. Both compounds have been undergoing human cancer clinical trials in Europe and North America. Based on the novel structure of LU103793, a series of analogs modified at the N-terminal dolavalyl moiety and -Pro-Pro-benzylamide unit was developed. These synthesized analogs were tested using a sulforhodamine B (SRB) assay for the drug-screening program at NCI on a variety of human cancer cell lines. As expected, most analogs exhibited potent and selective growth inhibition against leukemia. Analog 18 was specifically active against HL-60 and K-562 cell lines (GI₅₀s: 0.05 µm and 0.07 µm , respectively) while analogs 14 and 17 were selectively potent against prostate and breast cancer cell lines (GI₅₀s at micromolar levels). However, all analogs were less potent than 2 as growth inhibitors of some breast and colon cancer cell lines (e.g. MDA-MB-435 and HT-29). We believe that modification of novel marine natural products as synthetic analogs might show particular promise for developing novel anticancer candidates with moderate specificity.     

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.     

Exploration of imidazole and imidazopyridine dimers as anticancer agents: Design,synthesis, and structure–activity relationship study

Dimerization of proteins/receptors plays a critical role in various cellular processes, including cell proliferation and differentiation. Therefore, targeting such dimeric proteins/receptors by dimeric small molecules could be a potential therapeutic approach to treating various diseases, including inflammation‐associated diseases like cancer. A novel series of bis‐imidazoles ( 13–18 ) and bis‐imidazo[1,2‐a]pyridines ( 19–28 ) were designed and synthesized from Schiff base dimers ( 1–12 ) for their anticancer activities. All the synthesized compounds were screened for anticancer activities against three cancer cell lines, including cervical (HeLa), breast (MDA‐MB‐231), and renal cancer (ACHN). From structure–activity relationship studies, imidazo[1,2‐a]pyridines ( 19–28 ) showed remarkable cytotoxic activities, with compounds 19 and 24 showing the best inhibitory activities against all three cell lines. Especially, both 19 and 24 were very effective against the breast cancer cell line ( 19 , GI₅₀ = 0.43 µM; 24 , GI₅₀ = 0.3 µM), exceeding the activity of the control adriamycin (GI₅₀ = 0.51 µM). The in vivo anticancer activity results of compounds 19 and 24 were comparable with those of the animals treated with the standard drug tamoxifen. Therefore, the dimeric imidazo[1,2‐a]pyridine scaffold could serve as a potential lead for the development of novel anticancer agents.     

Design, synthesis and cytotoxicity of novel chalcone analogs derived from 1-cyclohexylpyrrolidin-2-one and 2,3-dihydrobenzo[f]chromen-1-one

Two divergent series of novel chalcone analogs, one derived from 1‐cyclohexylpyrrolidin‐2‐one and the other derived from 1‐benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1‐benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC₅₀ values between the range of 5 and 6 µM. With an IC₅₀ value of 3.4 µM, compound 4g was also active against human MDA‐MB‐435 melanoma cells. X‐ray structures of the β‐hydroxy ketone product ( 4a ) and the α,β‐unsaturated ketone ( 4h ) were collected, and confirm the syn‐configuration between the carbonyl moiety and the β‐vinylic proton in 4h . X‐ray structures of two 1‐cyclohexylpyrrolidin‐2‐one derivatives were also obtained, and both showed an E‐configuration for the double bond.     

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.     

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.     

Synthesis and Antitumor Activity of Novel Nitrogen Mustard‐Linked Chalcones

A series of nitrogen mustard‐linked chalcones were synthesized and evaluated for their antitumor activity in vitro against the K562 and HepG2 cell lines. The aldol condensation of [N,N‐bis(chloroethyl)‐3‐amino]‐acetophenone ( 2 ) with aromatic aldehydes afforded the nitrogen mustard‐linked chalcones. Among the analogs tested, compounds 5e and 5k exhibited significant anti‐proliferation activities against K562 cells with IC₅₀ values of 2.55 and 0.61 µM, respectively, which revealed higher cell toxicity than the standard drugs cisplatin (IC₅₀ > 200 µM) and adriamycin (IC₅₀ = 14.88 µM). The methoxyl and N,N‐dimethyl groups on the B‐ring of the chalcone frame enhanced the inhibitory activities against both the K562 and HepG2 cell lines. The structure–activity relationship study indicated that the inhibitory activities significantly varied with the position(s) and species of the substituted group(s).     

Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4 , 6 , 9 , 11 , 14–17 , 22 , 24 , and 25 were selected by the National Cancer Institute (NCI) to be screened for their in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compounds 4 , 6 , and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI₅₀ MG‐MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG‐MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin‐2‐one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI₅₀, TGI and LC₅₀ MG‐MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3 , 4 , 13 , 15 , 19 , 20 , and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4 , 5 , and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial‐anticancer agent.     

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.     

New quinazolinone-based derivatives as DHFR/EGFR-TK inhibitors: Synthesis,molecular modeling simulations,and anticancer activity

New 2-mercapto-quinazolin-4-one analogs were synthesized and tested for their in vitro anticancer activity, dihydrofolate reductase (DHFR) inhibition, and epidermal growth factor tyrosine kinase (EGFR-TK) inhibition activities. Compound 24 , which is characterized by a 2-benzyl-thio function, showed broad-spectrum anticancer activity with high safety profile and selectivity index. The concentrations of 24 causing 50% growth inhibition (GI₅₀) and total cell growth inhibition (TGI) and its lethal concentration 50 (LC₅₀) were 15.1, 52.5, and 91.2 µM, respectively, using 5-fluorouracil as a positive control. Also, it showed EGFR-TK inhibitory activity with IC₅₀ = 13.40 nM compared to gefitinib (IC₅₀ = 18.14 nM) and DHFR inhibitory potency with 0.30 μM compared to methotrexate (MTX; IC₅₀ = 0.08 μM). In addition, compound 24 caused cell cycle arrest and apoptosis on COLO-205 colon cancer cells. Compounds 37, 21 , and 54 showed remarkable DHFR inhibitory activity with IC₅₀ values of 0.03, 0.08, and 0.08 μM, respectively. The inhibitory properties of these compounds are due to an electron-withdrawing group on the quinazolinone ring, except for compound 54 . In a molecular modeling study, compound 24 showed the same binding mode as gefitinib as it interacted with the amino acid Lys745 via π–π interaction. Compound 37 showed a similar binding mode as MTX through the binding interaction with Lys68, Asn64 via hydrogen bond acceptor, and Phe31 via arene–arene interaction. The obtained model and substitution pattern could be used for further development.     

Design and synthesis of new 2,5-disubstituted-1,3,4-oxadiazole analogues as anticancer agents

In continuance of our search for new anticancer agents, we report herein the design, synthesis, and anticancer evaluation of oxadiazole analogues. Two series (4a-h and 4i-q) of new oxadiazole analogues were designed based on heterocyclic (1,3,4-oxadiazole)-linked aryl core of IMC-038525 (tubulin polymerization inhibitor), NSC 776715, and NSC 776715 and synthesized. All the compounds were fully characterized by infrared, nuclear magnetic resonance spectroscopy, and mass spectral data and the purity of compounds was checked by elemental analysis (C, H, and N analysis). Further seven compounds were evaluated for anticancer activity on nine different panels of 60 cell lines (60 NCI cancer cell lines) according to the National Cancer Institute screening protocol and percent growth and percent growth inhibition was calculated at 10?µM drug concentration. Ten compounds were evaluated for anticancer activity on two cancer cell lines (HeLa and MDA-MB-435) as per the standard protocol reported at four different drug concentrations (10^?7, 10^?6, 10^?5, and 10^?4?µM) and GI₅₀, LC₅₀, and TGI dose-related parameters were calculated. The compound 4j showed maximum anticancer activity at 10?µM, and was found to have higher sensitivity against MOLT-4, IGROV1, HCT-116, and K-562 with percent growth inhibitions of 50.38, 48.45, 46.26, and 46.26 respectively. The compound 4j showed superior anticancer activity than imatinib on 41 human cancer cell lines. The compound 4p showed anticancer activity with GI₅₀ of 36.7 and 46.5?µM against HeLa and MDA-MB-435 cell lines, respectively.