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.     

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.     

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 molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer

A novel series of 2-arylbenzothiazoles 9, 10 , and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10 , and 12 . Compounds 9d, 9f, 9i , and 9k exhibited potent multikinase inhibitory activity with IC₅₀ values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC₅₀ values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC₅₀ values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC₅₀ values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib ( III ), which showed IC₅₀ = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib ( III ), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Design,synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC₅₀ values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC₅₀ value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC₅₀ values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC₅₀ values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC₅₀ values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC₅₀ = 0.8 µM). These promising derivatives, 3f , 3h , and 3j , were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.     

A new series of thiazole-hydrazone hybrids for Akt-targeted therapy of non-small cell lung cancer

In an attempt to identify potent antitumor agents for the fight against non-small cell lung cancer, new thiazolyl hydrazones ( 2a–n ) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of the MTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2-[2-((Isoquinolin-5-yl)methylene)hydrazinyl]−4-(4-methylsulfonylphenyl)thiazole ( 2k ) (IC₅₀ = 1.43 ± 0.12 µM) and 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]−4-(1,3-benzodioxol-5-yl)thiazole ( 2l ) (IC₅₀ = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC₅₀ = 3.90 ± 0.10 µM) on A549 cell lines; 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]−4-(4-methoxyphenyl)thiazole ( 2j ) (IC₅₀ = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC₅₀ = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC₅₀ = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC₅₀ concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced-fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell lines via Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways.     

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.     

Novel pyrazolopyrimidine urea derivatives: Synthesis,antiproliferative activity,VEGFR-2 inhibition,and effects on the cell cycle profile

A series of novel diaryl urea pyrazolopyrimidine derivatives was designed and synthesized. All the synthesized compounds were evaluated for cytotoxic activity by the National Cancer Institute. A significant antiproliferative activity at a 10-µM dose was shown by four compounds ( 5c, 5e, 5g , and 5h ), and they were accordingly evaluated at five concentrations. They showed a potent and broad-spectrum antiproliferative activity, with GI₅₀ values between 0.553 and 3.80 µM and TGI values in the range of 2.17–100 µM. These four compounds potently inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) with IC₅₀ values in the nanomolar range. Molecular docking attributed their potent VEGFR-2 inhibitory activity to their interactions with key amino acids in the VEGFR-2 active site. Their flow cytometric analysis showed that they exerted their cytotoxic activity by reduction of the cellular proliferation and by induction of cell cycle arrest at the G2/M phase. Additionally, they induced DNA degradation or fragmentation, confirming the role of apoptosis in the cancer cell death and cytotoxicity induced by these compounds.     

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.     

New cytotoxic sesquiterpene lactones from Achillea cretica L. growing in Tunisia

The phytochemical study of Achillea cretica growing in Tunisia led to the isolation of two novel sesquiterpene lactones, which have been designated achicretin 1 and achicretin 2. Their chemical structures were further confirmed by mass spectroscopy (ESI-MS) and by extensive application of one- and two-dimensional NMR spectroscopy. The isolated compounds were tested for their cytotoxic activity against four human cancer cell lines, IGROV-1, OVCAR-3, MCF-7, and HCT-116 using the MTT assay. It has been found that achicretin 2 exhibited more potent inhibitory activity with IC₅₀ = values of 14.0 ± 1.0 and 16.0 ± 2.0 μM against OVCAR-3 and HCT-116 cells, respectively.     

Bioevaluation of synthetic pyridones as dual inhibitors of α-amylase and α-glucosidase enzymes and potential antioxidants

Herein, a library of novel pyridone derivatives 1–34 was designed, synthesized, and evaluated for α-amylase and α-glucosidase inhibitory as well as antioxidant activities. Pyridone derivatives 1–34 were synthesized via a one-pot multi-component reaction of variously substituted aromatic aldehydes, acetophenone, ethyl cyanoacetate, and ammonium acetate in absolute ethanol. Synthetic compounds 1–34 were structurally characterized by different spectroscopic techniques. Most of the tested compounds showed more promising inhibition potential than the standard acarbose (IC₅₀ = 14.87 ± 0.16 µM) but compounds 13 and 12 were found to be the most potent compounds with IC₅₀ values of 9.20 ± 0.14 µM and 3.05 ± 0.18 µM against α-amylase and α-glucosidase enzymes, respectively. Compounds 1–34 also displayed moderate antioxidant potential in the range of IC₅₀ = 96.50 ± 0.45 to 189.98 ± 1.00 µM in comparison to the control butylated hydroxytoluene (BHT) (IC₅₀ = 66.50 ± 0.36 µM), in DPPH radical scavenging activities. Additionally, all synthetic derivatives were subjected to a molecular docking study to investigate the interaction details of compounds 1–34 (ligands) with the active site of enzymes (receptors). These results indicate that the newly synthesized pyridone class may serve as promising lead candidates for controlling diabetes mellitus and as antioxidants.     

Design,synthesis, evaluation,and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors

A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC₅₀ value of 4.53 µM, followed by 8c (IC₅₀ = 5.12 µM), compared with the standard drug, orlistat (IC₅₀ = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a–f and 8a – f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of −163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π–π stacking and π–cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides ( 8a – d ) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.     

Novel 1,2,4-triazole derivatives: Design,synthesis, anticancer evaluation,molecular docking,and pharmacokinetic profiling studies

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including ¹H nuclear magnetic resonance (NMR) and ¹³C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure–activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC₅₀ value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC₅₀ value of 5.95 µM. The observed IC₅₀ values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.     

Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives

Seven benzylamino derivatives of podophyllotoxin 8a–8g were synthesized and their chemical structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT‐116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC₅₀ values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.     

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.     

Design,synthesis, and molecular docking studies of novel pyrazolyl 2‐aminopyrimidine derivatives as HSP90 inhibitors

A series of novel pyrazolyl 2‐aminopyrimidine derivatives ( 7a ‐ t ) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer activity. Several compounds exhibited potent HSP90 inhibition with IC₅₀ values less than that of the reference standard 17‐AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC₅₀ of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC₅₀ < 5 µM). 7t also induced dose dependent degradation of client proteins (pHER2 and pERK1/2) in Western blot analysis. Several structural features of 7p ‐ t oriented t he molecules to retain all the essential binding interactions with HSP90, as observed by rationalized docking studies. Therefore, the para‐nitrophenyl ring on the central pyrazole ring along with the 2‐amino group on the pyrimidine ring are the crucial features in the development of novel HSP90 inhibitors based on this scaffold for targeted anticancer therapy.     

Synthesis and cytotoxicity studies of novel 2-Hydrazonylpyrido[2,3-b]pyrazin-3(4H)-ones

In an attempt to develop potent antitumor agents, a series of novel 2‐hydrazonylpyrido[2,3‐b]pyrazin‐3(4H)‐one derivatives were designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, MDA‐MB‐231 and HT‐29 cell lines in vitro. Pharmacological data indicated that five of the target compounds showed cytotoxicity against A549 cell line below a concentration of 1 µM. Compound 15g was the most potent one with IC₅₀ values of 0.19, 2.11 and 2.15 µM against A549, MDA‐MB‐231 and HT29 cell lines, respectively.     

Synthesis,pharmacophore modeling,and cytotoxic activity of 2-thioxothiazolidin-4-one derivatives

A series of 2-thioxothiazolidin-4-one derivatives were efficiently synthesized and evaluated for their cytotoxic activity against four tumor cell lines. The synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data. Compound 5c exhibited notable in vitro anticancer activity against HeLa, HT29, A549, and MCF-7 cell lines with IC₅₀ values of 28.3, 24.5, 26.6, and 28.6 µM, respectively. Common pharmacophore model with H bond donor (2), H bond acceptor (3), Hydrophobic (1), and ring aromatic (2) was developed using phase module, and molecular docking of target compounds into the epidermal growth factor receptor kinase revealed important structural information on the plausible binding interactions.