Discovery of novel 1,5-benzodiazepine-2,4-dione derivatives as potential anticancer agents

A series of novel 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents were designed and synthesized using three-component reactions. The preliminary assays showed that most of them displayed moderate to good antitumor activities against human lung carcinoma (A549), human breast epithelial carcinoma (MCF-7), human colon carcinoma (HCT116), human cervical carcinoma (Hela) and Lewis lung carcinoma (2LL). Exhilaratingly, the activity level of 6m rivaled that of 5-Fluorouracil (5-Fu) against MCF-7 cell lines, which might be used as novel lead scaffold for potential anticancer development.     

Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents

The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacteriumtuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H(37)Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12-1.56μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents.     

Discovery of novel pyrazole derivatives as potential anticancer agents in MCL

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton’s tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC₅₀ values lower than 1?μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.     

Design,synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC₅₀ values of 0.48 ± 0.03 and 0.97 ± 0.13 μM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC₅₀ value of 3.3 µM, as compared to the standard drug colchicine (IC₅₀ = 9.1 μM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.     

Discovery of novel andrographolide derivatives as cytotoxic agents

The natural diterpenoid andrographolide (1) exhibits various biological activities. Seventeen derivatives of 1 were prepared via esterification and etherification of 14-dehydroxy-11,12-didehydroandrographolide (2). Most derivatives demonstrated significant inhibition against tumor cell growth. The most active compounds, 3b and 3c, had GI₅₀ values of 1.46–9.19 μM against A549, DU145, KB and KB-Vin tumor cells. In an immunocytochemical study, treatment with compound 3c disrupted microtubule dynamics in PC-3 cells, but caused no accumulation of metaphase cells, which is a phenotype dissimilar from that of 1. This difference suggests that structural modification of 1 resulted in a shift in the underlying molecular mechanism.     

Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents

Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.     

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC₅₀?=?0.67?±?0.09?µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.     

Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents

The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC₅₀) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem.2018, 61, 1704–1718), the conformation of the most active compounds determined by ¹H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.     

Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as potential anticancer agents

Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized and evaluated for biological activity. Preliminary investigations of antitumor activity in vitro showed that most of the synthesized compounds have significant antiproliferative effects on human cancer cell lines, such as BEL-7402, HeLa, and HCT116 with IC₅₀ values in the range of 0.13–60.23 μM without significant toxic effects on the non-cancerous human liver cell line L-02. In particular, compounds 4d and 4p were found to be the most potent against HeLa (4.20 μM) and HCT116 cells (0.13 μM), respectively, with superior or similar in vitro efficacy to that of the broad-spectrum anticancer drug taxol.     

Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC₅₀ values of 2.18/2.61?nM. Structure-activity relationship studies indicated that n-Pr served as R¹ group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R²?=?4-F) was benefited to the potency.     

Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.     

Molecular docking studies,biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt’s lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.     

Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies

A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC₅₀ values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC₅₀ values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket.     

Synthesis,biological evaluation,and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site

Abstract

A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC₅₀ value of 1.42?±?0.15?µM, as compared to cisplatin (IC₅₀?=?15.24?±?1.27?µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G₂/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC₅₀ value of 8.4?µM, which was slightly more active than the reference compound colchicine (IC₅₀?=?10.6?µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.     

Activated fly ash catalyzed facile synthesis of novel spiro imidazolidine derivatives as potential antibacterial and antifungal agents

An array of novel spiro imidazolidine derivatives was synthesized in dry media and was screened for their anti-microbial activities. Structure-activity relationship results revealed that compounds 22, 23 against P.aeruginosa, 24 against S.aureus, 24, 25 against K.pneumonia, 27 against S.aureus, β-H.streptococcus, 29 against M.luteus, K.pneumonia, 29, 30 against P.vulgaris exhibited excellent antibacterial activity at a minimum inhibitory concentration (MIC) value of 6.25 µg/mL. Compound 23 against M.gypseum, 25, 29 against Candida 6 and 29, 30 against C.albicans revealed excellent antifungal activity at a MIC value of 6.25 µg/mL.     

Synthesis and characterisation of celastrol derivatives as potential anticancer agents

In the present study, three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid, amine, and triazole derivatives. All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS, MGC-803, SGC-7901, HCT-116, A549, HeLa, BEL-7402, and HepG-2 cell lines. Most of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound 3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic amide, N-(R)-methyl-3-(1H-indol-2-yl)propanoate (11) showed considerable high anticancer activity against AGS cell lines, with an IC₅₀ value of 0.44?μM, and considerably higher activities against HCT-116, BEL-7402, and HepG-2 cell lines, with IC₅₀ values of 0.78, 0.63, and 0.76?μM, respectively. The results of apoptosis tests and molecular docking study of compound 11 binding to Caspase-3 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3.     

Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain

A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.     

Synthesis,biological evaluation and virtual screening of some acridone derivatives as potential anticancer agents

Eleven novel acridone derivatives were synthesized and evaluated for their anticancer activity against 60 human cancer cell lines. Five compounds 8b, 8d, 8g, 8h, and 8k displayed very good in vitro antiproliferative activities well over 95% of the panels. The most active compound is 8k (5, 7-dibromo-3-phenyl-3,4-dihydroacridin-1 (2H)-one). In addition, 8k was the most sensitive agent in all 9 panels starting with prostate (0.075 µm), leukemia (0.116 µm), non-small cell lung cancer (0.164 µm), colon cancer (0.193 µm), CNS cancer (0.264 µm), melanoma (0.317 µm), renal cancer (0.403 µm), ovarian cancer (0.410 µm), and breast cancer (0.608 µm). Virtual screening studies also revealed that nine of the eleven compounds formed good binding interaction with the active site ATPase domain of human topoisomerase IIα (PDB: 1zxm). All nine derivatives exhibited binding affinities that ranged in values from −8.5 to −7.9 kcal/mol, indicating that they could be catalytic inhibitors of the nuclear enzyme, topoisomerase.     

Synthesis, characterization and biological evaluation of some 16E-arylidene androstane derivatives as potential anticancer agents

A series of new 16E-arylidene androstane derivatives were synthesized and characterized. The new compounds were screened for their anticancer activities against the human cancer cell lines SW480, A549, HepG2 and HeLa in vitro using the MTT assay. The results of the in vitro study showed that a number of compounds have shown IC₅₀ values lower than 20 μM against the four cancer cell lines.