Design,synthesis, biological evaluation,and molecular docking of chalcone derivatives as anti-inflammatory agents

In this study, two series of 35 new chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piperazine fragment were synthesized and their structures were characterized by ¹H, ¹³C and ESI-MS. The in vivo and in vitro anti-inflammatory activities of target compounds were evaluated by using classical para-xylene-induced mice ear-swelling model and ELISA assays. Furthermore, docking studies were performed in COX-2 (4PH9). The in vivo anti-inflammatory assays indicated that most of the target compounds showed significant anti-inflammatory activities. Docking results revealed that the anti-inflammatory activities of compounds correlated with their docking results. Especially, compound 6o exhibited the most potent anti-inflammatory activity in vivo with the lowest docking score of ?17.4 kcal/mol and could significantly inhibit the release of LPS-induced IL-6 and TNF-α in a dose-dependent manner in vitro.     

Synthesis,biological evaluation and molecular docking studies of a new series of chalcones containing naphthalene moiety as anticancer agents

A series of chalcones containing naphthalene moiety 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro anticancer activity. The majority of the screened compounds displayed potent anticancer activity against both HCT116 and HepG2 human cancer cell lines. Among the series, compound 4h with a diethylamino group at the para position of the phenyl ring exhibited the most potent anticancer activity against HCT116 and HepG2 cell lines with IC₅₀ values of 1.20 ± 0.07 and 1.02 ± 0.04 μM, respectively. The preliminary structure–activity relationship has been summarized. Tubulin polymerization experiments indicated that 4h effectively inhibited tubulin polymerization and flow cytometric assay revealed that 4h arrests HepG2 cells at the G2/M phase in a dose-dependent manner. Furthermore, molecular docking studies suggested that 4h binds to the colchicine binding site of tubulin.     

Design,synthesis, biological evaluation and molecular docking of new uracil analogs-1,2,4-oxadiazole hybrids as potential anticancer agents

A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SO₃H as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, ¹H NMR, and ¹³C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human cancer cell lines: melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC₅₀ inferior to 1 µM. The possible mechanism of apoptosis induction by the derivatives was investigated using Annexin V staining, caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced apoptosis through caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the caspase-3 by forming a stable protein-ligand complex.     

Design,synthesis and molecular docking of substituted 3-hydrazinyl-3-oxo-propanamides as anti-tubercular agents

Based on the anti-mycobacterial activity of various acid hydrazides, a series of substituted 3-hydrazinyl-3-oxo-propanamides has been designed. The target compounds have been synthesized from diethylmalonate using substituted amines and hydrazine hydrate in ethanol. Computational studies and anti-tubercular activity screenings were undertaken to test their inhibitory effect on protein kinase PknB from Mycobacterium tuberculosis. Binding poses of the compounds were energetically favorable and showed good interactions with active site residues. Designed molecules obey the Lipinski’s rule of 5 and gave moderate to good drug likeness score. Among the sixteen compounds (1–16) taken for in silico and in vitro studies, 3 compounds (11, 12 and 15) have shown good binding energies along with exhibiting good anti-tubercular activity and thus may be considered as a good inhibitors of PknB.     

Synthesis,molecular modeling and biological evaluation of dithiocarbamates as novel antitubulin agents

A series of novel dithiocarbamate compounds with the chalcone scaffold have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and antitubulin polymerization inhibitors. Compound 2n showed the most potent biological activity in vitro, which inhibited the growth of MCF-7 cells with IC₅₀ of 0.04 ± 0.01 μM and the polymerization of tubulin with IC₅₀ of 6.8 ± 0.6 μM. To understand the tubulin–inhibitor interaction and the selectivity of the most active compound towards tubulin, molecular modeling studies were performed to dock compound 2n into the colchicine binding site, which suggested probable inhibition mechanism.     

Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents

Curcuminoids were isolated from Curcuma longa and their pyrazole and isoxazole analogues were synthesized and evaluated for antioxidant, COX-1/COX-2 inhibitory and anti-inflammatory activities. The designed analogues significantly enhance COX-2/COX-1 selectivity and possess significant anti-inflammatory activity in carrageenan induced rat paw edema assay. Pyrazole, isoxazole analogues of curcumin (4 and 7) exhibited higher antioxidant activity than trolox. Molecular docking study revealed the binding orientations of curcumin analogues in the active sites of COX and thereby helps to design novel potent inhibitors.     

Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents

A novel series of nitrogen-containing chalcones were synthesized by Mannich reaction and were screened for anti-inflammatory related activities such as inhibition of cyclooxygenase-2 (COX-2), trypsin and β-glucuronidase. The antioxidant potential was demonstrated using 1,1-diphenyl-2-picryl hydrazine (DPPH) radical scavenging activity. The results of the above studies shows that the compounds synthesized were found to be effective inhibitors of above pro-inflammatory enzymes, and were found to be possess moderate radical scavenging potential. Overall, the results of the studies reveal that the chalcones with N-methyl piperazine methyl and piperidine methyl substitution (4c, 3b, 4d, 6b) seems to be important for inhibition of β-glucuronidase. Whereas the chalcones with piperidine methyl substitution (8b, 7b, 7c, 6c, 4b, 3c, 3b) were observed as effective inhibitors of COX-2, while the same compounds were found to be less reactive against COX-1 as compared to COX-2.     

Design,synthesis and biological evaluation of substituted flavones and aurones as potential anti-influenza agents

We designed a series of substituted flavones and aurones as non-competitive H1N1 neuraminidase (NA) inhibitors and anti-influenza agents. The molecular docking studies showed that the designed flavones and aurones occupied 150-cavity and 430-cavity of H1N1-NA. We then synthesized these compounds and evaluated these for cytotoxicity, reduction in H1N1 virus yield, H1N1-NA inhibition and kinetics of inhibition. The virus yield reduction assay and H1N1-NA inhibition assay demonstrated that the compound 1f (4-methoxyflavone) had the lowest EC₅₀ of 9.36 nM and IC₅₀ of 8.74 μM respectively. Moreover, kinetic studies illustrated that compounds 1f and 2f had non-competitive inhibition mechanism.     

5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design,synthesis, molecular docking and evaluation

In continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli. The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium, followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E. coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results.     

Synthesis,biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents

Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5–9 against primary ALL-5 (IC₅₀ = 5.3–14 nM), 5, 7–9 against A549 (IC₅₀ = 10 nM), 5, 7–9 against MCF-7 (IC₅₀ = 11 nM), 5–9 against LoVo (IC₅₀ = 7–12 nM), and 5, 7–9 against LoVo/DX (IC₅₀ = 48–87 nM). These IC₅₀ values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.     

Synthesis,molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors

In this study, a new series of benzimidazole and bisbenzimidazole derivatives were prepared via the reaction of iminoester hydrochlorides and o-phenylenediamines and then screened for their lipase inhibition properties. Among the synthesized molecules, compounds 7a, 8a and 8c showed the best inhibitory effect against lipase enzyme with IC₅₀ values of 1.72 ± 0.12 µM, 1.92 ± 0.28 and 0.98 ± 0.07 µM, respectively. Moreover, molecular modeling studies were performed in order to understand to the inhibitory activity of the molecules. Binding poses of the studied compounds were determined at the target sites using induced fit docking (IFD) algorithms.     

Design,synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors

Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen–Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC₅₀ at 4 μM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI₅₀ at 9 μM) on breast cancer cell line, MCF-7.     

Antiproliferative 3-deoxysphingomyelin analogs: Design,synthesis, biological evaluation and molecular docking of pyrrolidine-based 3-deoxysphingomyelin analogs as anticancer agents

Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI₅₀ values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies.     

Ugi efficient synthesis,biological evaluation and molecular docking of coumarin-quinoline hybrids as apoptotic agents through mitochondria-related pathways

Ugi reaction was a reliable procedure for the synthesis of new coumarin-quinoline frameworks. Excellent yields, mild reaction conditions and easily available and inexpensive starting materials are advantages of this protocol. Cytotoxic effects of fourteen products were investigated in A2780 human ovarian cancer cells. Two synthesized compounds (L11 and L12) exhibited more anti-cancer activity than other derivatives with IC₅₀ values of 0.042 mmol/L and 0.102 mmol/L, respectively and were thus selected for further studies. Apoptosis was induced through the intrinsic pathway by activating caspase 9 and ended at the executioner pathway of caspase 3. Measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also carried out for both of them. Further studies on a mechanism by Real Time-PCR and Western blot analysis were performed for anti-apoptotic proteins Bcl-2 and survivin both in mRNA and protein level relating to the untreated A2780 cells. The treatment of A2780 cells with compound L11 significantly (P-value ≤ 0.05) induced apoptosis by down-regulation of Bcl-2 and survivin both in mRNA and protein level via a single dose (0.042 mmol/L), as well as activation of caspase 9 and 3, loss of MMP, and high ROS. Accordingly, findings supported the first report under which the pro-apoptotic activity of compound L11 as an apoptosis-inducing agent was related to mitochondrial-mediated dysfunction signaling pathways. Molecular docking supports experimental outcomes. Evidently, coumarin-quinoline scaffolds are potentially favorable options for further assessment as influential chemotherapeutic agents for the future.     

Design,synthesis, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers

Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a–e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5′-(morpholinosulfonyl) spiro [chromene-2, 3′-indolin]-2′-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3–b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, ¹H NMR, ¹³C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC₅₀ values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32–19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC₅₀ values are from 0.019 to 0.026 µM while IC₅₀ of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.     

Design, synthesis, and biological evaluation of thiophene analogues of chalcones

Chalcones are characterized by possessing an enone moiety between two aromatic rings. A series of chalcone-like agents, in which the double bond of the enone system is embedded within a thiophene ring, were synthesized and evaluated for antiproliferative activity and inhibition of tubulin assembly and colchicine binding to tubulin. The replacement of the double bond with a thiophene maintains antiproliferative activity and therefore must not significantly alter the relative conformation of the two aryl rings. The synthesized compounds were found to inhibit the growth of several cancer cell lines at nanomolar to low micromolar concentrations. In general, all compounds having significant antiproliferative activity inhibited tubulin polymerization with an IC(50)<2microM. Several of these compounds caused K562 cells to arrest in the G2/M phase of the cell cycle.     

Synthesis and biological evaluation of indolyl chalcones as antitumor agents

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b–d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC₅₀ values 0.03 and 0.09 μM, against PaCa-2 cell line, respectively.     

Design,synthesis and biological evaluation of new carbazole derivatives as anti-cancer and anti-migratory agents

Based on the efficacy of EHop-016 as an inhibitor of migration and Rac1 activation, a new series of carbazole derivatives has been synthesized. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. Preliminary investigations of their anticancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI₅₀ values in the range of 13–50?µM. Furthermore, compounds 3b and 11b inhibit migration activity of metastatic cell line MDA-MB-231 by 32% and 34%, respectively. Compound 11b was shown to inhibit activation of the Rho GTPase Rac1 by 55% at 250?nM in both MDA-MB-231 and MDA-MB-435 cell lines. Compared with the IC₅₀ of Rac1 inhibition by lead compound EHop-016 of 1.1?µM, compound 11b demonstrates 4X improved in vitro efficacy.