Synthesis,in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC₅₀ values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver–Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn’t show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer’s disease.     

Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents

As a part of our project aimed at developing new safe chemotherapeutic agents against tropical diseases, a series of aryl derivatives of 2- and 3-aminoquinoline, some of them new compounds, was designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas’ disease), and Leishmania mexicana, the etiological agent of Leishmaniasis. Some of them showed a remarkable activity as parasite growth inhibitors. Fluorine-containing derivatives 11b and 11c were more than twice more potent than geneticin against intracellular promastigote form of Leishmania mexicana exhibiting both IC₅₀ values of 41.9 μM. The IC₅₀ values corresponding to fluorine and chlorine derivatives 11b–d were in the same order than benznidazole against epimastigote form. These drugs are interesting examples of effective antiparasitic agents with outstanding potential not only as lead drugs but also to be used for further in vivo studies. In addition, the obtained compounds showed no toxicity in Vero cells, which makes them good candidates to control tropical diseases. Regarding the probable mode of action, assayed quinoline derivatives interacted with hemin, inhibiting its degradation and generating oxidative stress that is not counteracted by the antioxidant defense system of the parasite.     

Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase

In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q) were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 10⁴, 2.22 × 10⁴, 1.18 × 10⁴, 9.8 × 10³ and 3.2 × 10⁴ M⁻¹ and free energy change as −5.83, −5.91, −5.51, −5.41 and −6.12 kcal M⁻¹ at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.     

Design,synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC₅₀ value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC₅₀ values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.     

Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design,synthesis and biological evaluation

A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu²⁺-induced Aβ_1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC₅₀ value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu²⁺-induced Aβ_1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu²⁺-induced Aβ_1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.     

Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents

This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1–3) as potential candidates to counteract neuroinflammation processes in Alzheimer’s disease.GPE 1–3 pseudotripeptides are synthetic derivatives of Gly-l-Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t_1/2?>?4?h) than GPE (t_1/2?=?30?min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1–3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ_25–35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties.     

Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents

A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.     

Synthesis and biological evaluation of 2-arylbenzofuran derivatives as potential anti-Alzheimer’s disease agents

Alzheimer''s disease (AD) is a type of progressive dementia caused by degeneration of the nervous system. A single target drug usually does not work well. Therefore, multi-target drugs are designed and developed so that one drug can specifically bind to multiple targets to ensure clinical effectiveness and reduce toxicity. We synthesised a series of 2-arylbenzofuran derivatives and evaluated their in vitro activities. 2-Arylbenzofuran compounds have good dual cholinesterase inhibitory activity and β-secretase inhibitory activity. The IC₅₀ value of compound 20 against acetylcholinesterase inhibition (0.086 ± 0.01 µmol·L⁻¹) is similar to donepezil (0.085 ± 0.01 µmol·L⁻¹) and is better than baicalein (0.404 ± 0.04 µmol·L⁻¹). And most of the compounds have good BACE1 inhibitory activity, of which 3 compounds (8, 19 and 20) show better activity than baicalein (0.087 ± 0.03 µmol·L⁻¹). According to experimental results, 2-arylbenzofuran compounds provide an idea for drug design to develop prevention and treatment for AD.     

Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis

This article describes discovery of a novel and new class of cholinesterase inhibitors as potential therapeutics for Alzheimer’s disease. A series of novel isoalloxazine derivatives were synthesized and biologically evaluated for their potential inhibitory outcome for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds exhibited high activity against both the enzymes AChE as well as BuChE. Of the synthesized compounds, the most potent isoalloxazine derivatives (7m and 7q) showed IC₅₀ values of 4.72 μM and 5.22 μM respectively against AChE; and, 6.98 μM and 5.29 μM respectively against BuChE. These two compounds were further evaluated for their anti-aggregatory activity for β-amyloid (Aβ) in presence and absence of AChE by performing Thioflavin-T (ThT) assay and Congo red (CR) binding assay. In order to evaluate cytotoxic profile of these two potential compounds, cell viability assay of SH-SY5Y human neuroblastoma cells was performed. Further, to understand the binding behavior of these two compounds with AChE and BuChE enzymes, docking studies have been reported.     

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.     

Design,synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents

A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC₅₀ value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC₅₀ values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.     

Synthesis and biological evaluation of quinoline derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors

In this work, a series of quinoline derivatives were designed and synthesized as antitumor agents. Most quinolines showed potent anti-proliferative activity against human prostatic cancer PC-3 cell line. Among which, 9d, 9f and 9g were the most effective compounds with GI₅₀ values of 2.60, 2.81 and 1.29 μM, respectively. Structure–activity relationship analysis indicated that the secondary amine linked quinoline and pyridine ring played an important role in the anti-proliferative effects. Mechanistic studies revealed that 9g was a potential Pim-1 kinase inhibitor with abilities of cell cycle arrest and apoptosis induction. Considering of the increased activity of Pim-1 in prostate cancer, such compounds have potential to be developed as anti-prostate cancer agents.     

Discovery of novel isoflavone derivatives as AChE/BuChE dual-targeted inhibitors: synthesis,biological evaluation and molecular modelling

AChE and BuChE are druggable targets for the discovery of anti-Alzheimer’s disease drugs, while dual-inhibition of these two targets seems to be more effective. In this study, we synthesised a series of novel isoflavone derivatives based on our hit compound G from in silico high-throughput screening and then tested their activities by in vitro AChE and BuChE bioassays. Most of the isoflavone derivatives displayed moderate inhibition against both AChE and BuChE. Among them, compound 16 was identified as a potent AChE/BuChE dual-targeted inhibitor (IC₅₀: 4.60?μM for AChE; 5.92?μM for BuChE). Molecular modelling study indicated compound 16 may possess better pharmacokinetic properties, e.g. absorption, blood–brain barrier penetration and CYP2D6 binding. Taken together, our study has identified compound 16 as an excellent lead compound for the treatment of Alzheimer’s disease.     

Synthesis and SAR study of novel sarsasapogenin derivatives as potent neuroprotective agents and NO production inhibitors

Sarsasapogenin, isolated from rhizomes of Anemarrhena asphodeloides, was found to be able to enhance memory. On the basis of the structure of Sarsasapogenin, a series of derivatives were synthesized and evaluated for their neuroprotective activity in PC12 cells and NO production inhibitory activity in RAW264.7 cell lines. The preliminary structure-activity relationship of them indicated that introduction of carbamate groups at the 3-hydroxyl position of sarsasapogenin might improve neuroprotective activity. Some synthesized derivatives such as AA3, AA4, AA9 and AA13 exhibited both notably neuroprotective activity and NO production inhibitory activity.     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Synthesis and biological evaluation of 21-arylidenepregnenolone derivatives as neuroprotective agents

A series of 21-arylidenepregnenolone derivatives and their corresponding epoxides were synthesized. The neuroprotective effects of these steroidal compounds against amyloid-β(25-35) (Aβ(25-35))- and hydrogen peroxide (H(2)O(2))-induced neurotoxicity in PC12 cells, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells were evaluated. The bioassay results indicated that several 3β-pregn-21-benzylidene-20-one derivatives displayed potent in vitro neuroprotective effects in different screening models, for example, compounds 2b, 3a, 3b, and 3s showing significant activities against Aβ(25-35)-induced neurotoxicity in PC12 cells, 2b showing significant activities against H(2)O(2)-induced neurotoxicity in PC12 cells, and 2g, 3b, and 3e showing potent protection against OGD insult. The results suggested that introduction of an arylidene group into steroidal nucleus played an important role in neuroprotective activity, while the formation of epoxy group at C-5,6 could be also important for the neuroprotective activity in some degree. The pharmacological data reported here are helpful for the design of novel steroidal neuroprotective candidates.     

Design,synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents

A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC₅₀ value ranging between 1.0?±?0.01 and 72?±?2.8?μM when compared with the standard donepezil (IC₅₀, 2.63?±?0.28?μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC₅₀ values of 1.0, 1.0 and 1.8?μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.     

Synthesis and biological evaluation of novel 4,7-dihydroxycoumarin derivatives as anticancer agents

A series of novel 4,7-dihydroxycoumarin based acryloylcyanohydrazone derivatives were synthesized and evaluated for antiproliferative activity against four different cancer cell lines (A549, HeLa, SKNSH, and MCF7). Most of the compounds displayed potent cytotoxicity with IC₅₀ values ranging from 3.42 to 31.28 µM against all the tested cancer cell lines. The most active compound, 8h was evaluated for pharmacological mechanistic studies on cell cycle progression and tubulin polymerization inhibition assay. The results revealed that the compound 8h induced the cell cycle arrest at G2/M phase and inhibited tubulin polymerization with IC₅₀ = 6.19 µM. Experimental data of the tubulin polymerization inhibition assay was validated by molecular docking technique and the results exhibited strong hydrogen bonding interactions with amino acids (ASN-101, TYR-224, ASN-228, LYS-254) of tubulin.     

Design,synthesis and biological evaluation of novel aryl-acrylic derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors

Two series of novel aryl-acrylic derivatives were designed, synthesized, and screened in enzymatic and cellular inhibitory activities. All compounds showed moderate to significant potency. The SAR analyses indicated that the semicarbazone linker is better than the 1,2,3-triazole linker. Among semicarbazone compounds that R₁ bearing di-chain amino groups exhibited superior activities to those with morpholino group. Furthermore, compounds with electron-withdrawing groups at the 2-position or 4-position on the terminal phenyl ring were more active. Among these, compounds 7g, 7i, 7m and 7n exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against normal HeLa cells. In addition, the study suggested that the aryl-acrylic is an interesting novel scaffold for IDO1 inhibition for further development.     

Synthesis and biological evaluation of novel trichodermin derivatives as antifungal agents

To discover more potential antifungal agents, 17 novel trichodermin derivatives were designed and synthesized by modification of 3 and 4a. The structures of all the synthesized compounds were confirmed by ¹H NMR, ESI-MS and HRMS. Their antifungal activities against Ustilaginoidea oryzae and Pyricularia oryzae were evaluated. Most of the target compounds showed potent inhibitory activity, in which 4g showed superior inhibitory effects than 4a and commercial fungicide prochloraz. Furthermore, 4h demonstrated comparable inhibitory activity to 4a. Moreover, 4i and 4l exhibited excellent inhibitory activity for Pyricularia oryzae. Additionally, compound 9 was found to be more active against all tested fungal strains than 3, with EC₅₀ values of 0.47 and 3.71 mg L⁻¹, respectively.