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 Biological Evaluations of 1,2‐Diaryl Pyrroles as Analogues of Combretastatin A‐4

A series of novel 1,2‐diaryl pyrroles as analogues of combretastatin A‐4 ( CA‐4, 1a ) were synthesized and evaluated for their antitumour potential against three cancer cell lines. Most compounds exhibited growth inhibition against all of the cancer cell lines. Compound 7q not only exhibited prominent antitumour efficacy with IC₅₀ values of 0.390 μm in SGC‐7901, 0.070 μm in HT‐1080 and 0.045 μm in KB cell lines but also showed low activity with IC₅₀ values of 30.08 μm in normal L929 cell line. Moreover, compound 7q inhibited tubulin polymerization into microtubules and caused microtubule destabilization. A molecular docking study of 7q was performed to determine its binding mode at the colchicine site in the tubulin dimer.     

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 of New Congeners of 1‐methyl‐3‐aminoisoquinolines,Evaluation of Their Cytotoxic Activity,In Silico and In Vitro Study of Their Molecular Targets as PDE4B

To examine the cytotoxic activity of congeners of 3‐amino‐isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N‐(6,7‐dimethoxy‐1‐methyl‐isoquinolin‐3‐yl)‐4‐{[(1‐ethyl‐4‐methyl‐1H‐pyrazol‐3‐yl)methyl]amino}benzamide ( 4d )) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT‐116 cells (IC₅₀ = 18 μm ) and human breast cancer T‐47D cells (GI₅₀ = 1.9 μm ). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 μm of 4c and 4d inhibited the growth of HKe3‐mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture.     

Design and synthesis of new 2‐anilinoquinolines bearing N‐methylpicolinamide moiety as potential antiproliferative agents

A series of new 2‐anilinoquinolines 6a – o possessing the substantial N‐methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF‐7, SK‐BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c , 6d , 6j , 6k , and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five‐dose testing mode to determine their GI₅₀ values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4‐chloro‐3‐trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI₅₀ values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA‐MB‐468, renal A498, and melanoma SK‐MEL‐5 and UACC‐62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF‐1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B‐Raf^V600E and C‐Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.     

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.     

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.     

7‐Chloroquinoline–isatin Conjugates: Antimalarial,Antitubercular, and Cytotoxic Evaluation

A series of twenty piperazine‐tethered 7‐chloroquinoline–isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl‐mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine‐resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC₅₀ of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.     

Design, synthesis, and in vitro evaluation of cytotoxic activity of new substituted 1,4-benzoquinones and hydroquinones

A new series of p-benzoquinones, hydroquinones, and quinol dimethyl ethers substituted by a pyrazole ring either directly or after an oxoethyl linker was synthesized and screened for in vitro cytotoxic activity. Compounds 8d, f, g, i, and 9c, f, and 13c exhibited broad-spectrum activity (GI₅₀ MG-MID values 9.27–14.72 μM). With regard to sensitivity, compounds 8f and 9c, f have proved to possess a remarkable activity against leukemia tumor cell lines (GI₅₀ = 3.43–5.03 μM). Indeed, compound 13c showed the highest activity profile against individual leukemia subpanel cell line SR (GI₅₀ = 0.91 μM).     

Synthesis and Biological Evaluation of Mercapto Triazolo‐Benzothiadiazine Linked Aminobenzothiazoles as Potential Anticancer Agents

The synthesis of a series of 10‐substituted 5,5‐dioxo‐5,10‐dihydro[1,2,4]triazolo[4,3‐b][1,2,4]benzothiadiazine coupled with sulfanylacetamido benzothiazole pharmacophores ( 5a – g ) is described. All the synthesized compounds have been evaluated for their anticancer activity. Most of the compounds showed significant growth inhibitory activity against selected human tumor cell lines. Interestinlgy, one of the synthesized compounds 5d, exhibited GI₅₀ values of 1.4 and 2.1 μm against RPMI‐8226 (leukemia) and HOP‐62 (lungs) cell lines, respectively.     

Design,synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold

A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC‐3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10 nm . Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC‐3 cell line and displayed fivefold higher antiproliferative activity against PC‐3 cell line with IC₅₀ value of 3.1 ± 0.1 μm than positive control (15.5 ± 0.4 μm ). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).     

Design,Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

A series of novel hybrids of indole–pyrimidine‐containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT‐29, A549, MDA‐MB‐231 and MCF‐7. Particularly, the most promising compound 34 showed more potent and broad‐spectrum cytotoxic activities with the IC₅₀ values ranged from 5.01 to 14.36 μm against A549, MDA‐MB‐231 and MCF‐7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC₅₀ value of 11.2 μm . Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine‐binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK‐293. These results suggest that this novel class of indole–pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.     

Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives

A series of shikonin derivatives ( 1 – 13 ) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 3‐(1H‐indol‐3‐yl)propanoate) and compound 8 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 2‐(thiophen‐3‐yl)acetate) exhibited good antiproliferative activity of A875 (IC₅₀ = 0.005 ± 0.001 μm , 0.009  ± 0.002 μm ) and HeLa (IC₅₀ = 11.84 ± 0.64 μm , 4.62  ± 0.31 μm ) cancer cell lines in vitro, respectively. Shikonin (IC₅₀ = 0.46 ± 0.002 μm , 4.80 ± 0.48 μm ) and colchicine (IC₅₀ = 0.75 ± 0.05 μm , 17.79 ± 0.76 μm ) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC₅₀ of 3.96  ± 0.13 μm and 3.05 ± 0.30 μm , respectively), which were compared with shikonin (IC₅₀ =  15.20 ± 0.25 μm ) and colchicine (IC₅₀ = 3.50 ± 0.35 μm ). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Synthesis and In‐Vitro Cytotoxicity Evaluation of Novel Naphtindolizinedione Derivatives,Part II: Improved Activity for Aza‐Analogues

Our previous investigation on potential antitumor agents now got enriched by the evaluation of in‐vitro activity against a full panel of NCI cancer cell lines for five new compounds. The concurrent presence in the molecular structure of a nitrogen atom in the aromatic system and a N,N‐dimethylaminoethyl amide chain play a decisive role to enhance cytotoxicity. The N,N‐anti compound 14 shows a higher activity than its N,N‐syn isomer, exhibiting the best selective inhibition against the melanoma MALME‐3M cell line, with a GI₅₀‐value (= 30 nM) corresponding to a 330‐fold increase in activity compared to the corresponding deaza‐analogue. Compound 14 is efficiently synthesized by aminolysis of the ester obtained as a single regio‐isomer by an one‐pot three‐component procedure involving metal‐assisted cyclization under microwave irradiation conditions.     

Design,Synthesis, and Biological Evaluation of 1‐Benzyl‐1H‐pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors

Receptor interacting protein 1 (RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1‐(2,4‐dichlorobenzyl)‐3‐nitro‐1H‐pyrazole ( 1a ). A number of 1‐benzyl‐1H‐pyrazole derivatives were synthesized and structure‐activity relationship (SAR) analysis led to the discovery of a potent compound, 4b , which showed a K_d value of 0.078 μm against the RIP1 kinase and an EC₅₀ value of 0.160 μm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l ‐arginine‐induced pancreatitis mouse model.     

Evaluation of Novel N‐(piperidine‐4‐yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells

In this study, a series of novel N‐(piperidine‐4‐yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC₅₀ value of 0.25 μm . Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p‐Rb and enhanced the expression of p21, p53, Rb, and phospho‐adenosine monophosphate‐activated protein kinase (p‐AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21‐dependent pathway.     

Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

Design,Synthesis, and In Vitro Evaluation of Novel 3, 7‐Disubstituted Coumarin Derivatives as Potent Anticancer Agents

Twenty‐seven 3, 7‐disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate‐to‐potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI₅₀) against SN12C, OVCAR, BxPC‐3, KATO‐III, T24, SNU‐1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3‐position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents.