Design,synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors

A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC₅₀ values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents.     

Synthesis,SAR elucidations and molecular docking study of newly designed isatin based oxadiazole analogs as potent inhibitors of thymidine phosphorylase

Thymidine phosphorylase is an enzyme involved in pyrimidine salvage pathway that is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is enormously up regulated in a variety of solid tumors. Furthermore, surpassing of TP level protects tumor cells from apoptosis and helps cell survival. Thus TP is identified as a prime target for developing novel anticancer therapies. A new class of exceptionally potent isatin based oxadiazole (1–30) has been synthesized and evaluated for thymidine phosphorylase inhibitory potential. All analogs showed potent thymidine phosphorylase inhibition when compared with standard 7-Deazaxanthine, 7DX (IC₅₀ = 38.68 ± 1.12 µM). Molecular docking study was performed in order to determine the binding interaction of these newly synthesized compounds, which revealed that these synthesized compounds established stronger hydrogen bonding network with active site of residues as compare to the standard compound 7DX.     

Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents

Three novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1–64?µg/mL. Compounds 4b and 4c presented the most potent inhibitory activity against Gram-positive bacteria (S. aureus 4220, MRSA 3167, QRSA 3519) and Gram-negative bacteria (E. coli 1924), with minimum inhibitory concentration values of 1 or 2?µg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. The cytotoxic activity of the compounds 4a, 4b, 4c and 11n were assessed in L02 cells. In vitro enzyme study implied that compound 4c exerted its antibacterial activity through DHFR inhibition.     

Design,synthesis, anti-schistosomal activity and molecular docking of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives

Schistosomiasis remains one of the most prevalent parasitic infections and has significant public health consequences. Praziquantel (PZQ) is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Herein we report a series of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives, which were synthesized, characterized and tested as anti-schistosomal agents in vitro. Among all tested compounds, compounds 4a, 5b, and 7b at different tested concentrations (50, 100, and 200 μg/mL) showed the highest schistosomicidal activity. Among those 3 compounds, compound 7b was the most potent anti-schistosomal one. Moreover, all tested compound, at 50 μg/mL concentration, significantly reduced oviposition of adult worms in vitro. Furthermore, both compound 4a and 7b, as well as compound 6a, completely diminished egg deposition. To clarify the possible mechanism by which novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives act as anti-schistosomal agents, molecular docking of all new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal agents. The docking results revealed moderate to high affinity of the new compounds towards TGR. Compound 7b scored the highest binding energy (−101.13 kcal/mol) against TGR crystal structure forming eight hydrogen bonds with the amino acid residues at the binding site of the receptor. This result indicates that compound 7b could exert its effect through inhibition of TGR, which is a vital enzyme for schistosome survival.     

Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

Syntheses and characterization of non-bisphosphonate quinoline derivatives as new FPPS inhibitors

Background

Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs.

Methods

The following methods were used: organic syntheses of non-bisphosphonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays.

Results

We report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound 6b showed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound 6b to FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that 6b could possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells.

Conclusions

Our results showed that quinoline derivative 6b could become a new lead compound for further optimization for cancer treatment.

General significance

The traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphosphonate FPPS inhibitors with good cell membrane permeability is potentially important.     

Antibacterial activities against Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae of 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives

In this letter, a variety of simple 6-chloro-4-(4-substituted piperazinyl)quinazoline derivatives was prepared. Preliminary bioassays revealed that these compounds showed good antibacterial activities toward phytopathogens Ralstonia solanacearum and Xanthomonas oryzae pv. oryzae (Xoo). Among these derivatives, compounds 5a, 5d, 5e, 5f, 5p, 5q, 6b, and 6d exhibited potent inhibition effects against R. solanacearum with EC₅₀ within 4.60–9.94 µg/mL, especially, compound 5g exerted the strongest activity with EC₅₀ of 2.72 µg/mL; compound 6b possessed the best inhibitory activity toward Xoo with EC₅₀ of 8.46 µg/mL. Subsequently, a good predictive three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed via CoMFA to direct the future structural modification and optimization. Furthermore, the pathogens’ topological studies were performed to explore the possible antibacterial mechanism. Given their simple frameworks and facile synthesis, title compounds can serve as the potential antibacterial leads.     

Design,synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors

Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC₅₀ of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC₅₀ of 329 nM and EBC-1 IC₅₀ of 479 nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization.     

Design,synthesis and molecular docking of pyrazolo [3,4d] thiazole hybrids as potential anti-HIV-1 NNRT inhibitors

A series of pyrazolo[3.4,d]thiazole hybrids 6 were synthesized from 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5. The 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5 were synthesized from 2-amino-4-arylthiazoles 1 and 2-chloro-acetamido-4-arylthiazoles 2 via the formation of 2-imino-3-(4-substituted-arylthiazol-2-yl)-thiazolidin-4-ones 3 using substituted aldehydes 4. The 5-acrylidene derivative 5 on cyclisation with phenyl hydrazine give the pyrazolo [3, 4, d] thiazole derivatives 6. The obtained pyrazolo [3.4, d]thiazole derivatives were studied as anti-HIV-1 NNRT inhibitors. It was found that these compounds might have potent RT inhibition activity.     

Identification of 1,2,4-triazoles as new thymidine phosphorylase inhibitors: Future anti-tumor drugs

Thymidine phosphorylase (TP) is over expressed in several solid tumors and its inhibition can offer unique target suitable for drug discovery in cancer. A series of 1,2,4-triazoles 3a–3l has been synthesized in good yields and subsequently inhibitory potential of synthesized triazoles 3a–3l against thymidine phosphorylase enzyme was evaluated. Out of these twelve analogs five analogues 3b, 3c, 3f, 3l and 3l exhibited a good inhibitory potential against thymidine phosphorylase. Inhibitory potential in term of IC₅₀ values were found in the range of 61.98 ± 0.43 to 273.43 ± 0.96 μM and 7-Deazaxanthine was taken as a standard inhibitor with IC₅₀ = 38.68 ± 4.42 μM. Encouraged by these results, more analogues 1,2,4-triazole-3-mercaptocarboxylic acids 4a–4g were synthesized and their inhibitory potential against thymidine phosphorylase was evaluated. In this series, six analogues 4b–4g exhibited a good inhibitory potential in the range of 43.86 ± 1.11–163.43 ± 2.03 μM. Angiogenic response of 1,2,4-triazole acid 4d was estimated using the chick chorionic allantoic membrane (CAM) assay. In the light of these findings, structure activity relationship and molecular docking studies of selected triazoles to determine the key binding interactions was discussed. Docking studies demonstrate that synthesized analogues interacted with active site residues of thymidine phosphorylase enzyme through π-π stacking, thiolate and hydrogen bonding interactions.     

1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design,synthesis, COX-1/2 inhibitory activity and molecular docking study

The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a–o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a–o) were synthesized using a two-step scheme, and their chemical structures were confirmed with ¹H NMR, ¹³C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC₅₀ 0.04–0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC₅₀ 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates.     

Synthesis,and anti-proliferative,Pim-1 kinase inhibitors and molecular docking of thiophenes derived from estrone

Heterocyclization of steroids were reported to give biologically active products where ring D modification occured. Estrone (1) was used as a template to develop new heterocyclic compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine and elemental sulfur gave the thiophene derivative 3. The latter compound reacted with acetophenone derivatives 4a-c to give the hydrazide-hydrazone derivatives 5a-c, respectively. In addition, compound 3 formed thiazole derivatives through its first reaction with phenylisothiocyanate to give the thiourea derivative 9 followed by the reaction of the later with α-halocarbonyl compounds. In the present work a series of novel estrone derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). The most promising compounds 5b, 5c, 11a, 13c, 15b, 15c, 15d, 17a and 17b were further investigated against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR. Compounds 5b, 15d, 17a and 17b were selected to examine their Pim-1 kinase inhibition activity where compounds 15d and 17b showed high activities. Molecular docking of some of the most potent compounds was demonstrated.     

Synthesis,anti-thymidine phosphorylase activity and molecular docking of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones

In our lead finding program, a series of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones and their 5-thio-alkyl derivatives were designed and synthesized which contained different substituents at ortho-position of 2-phenyl ring attached to the fused ring structure. The preliminary pharmacological evaluation demonstrated that the synthesized compounds exhibited a varying degree of inhibitory activity towards thymidine phosphorylase (TP), comparable to reference compound, 7-Deazaxanthine (7-DX, 2) (IC₅₀ value = 42.63 μM). The study also inferred that the ortho-substituted group at the phenyl ring and 5-thio-alkyl moiety imparted steric hindrance effects in the binding site of the enzyme, leading to a reduced inhibitory response. In addition, compound 3a was identified as a mixed-type inhibitor of TP. Moreover, computational docking study was performed to illustrate the important structural information on the plausible ligand-enzyme binding interactions.     

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,molecular modelling and biological evaluation of tetrasubstituted thiazoles towards cholinesterase enzymes and cytotoxicity studies

Alzheimer is a neurodegenerative disease and requires the development of new scaffold to treat it. In this regard, thiazoles derivative are playing their significant role. In the current research paper we have focused our attention for the development of tetrasubstituted thiazole (3a-h) derivatives using domino synthesis by mixing the thiourea as a precursor, with acetophenone in the presence of iodine and tosic acid in DMSO and refluxed for 12–22 h. The structures of the newly synthesized compounds were confirmed by FTIR, ¹H NMR, ¹³C NMR and EIMS analysis. Thiazole derivatives were analyzed for their biological significances against acetyl and butylcholinesterase enzymes and compound 3b and 3d were found more active against these enzyme, respectively. The mode of inhibition was determined for the potent compounds against both the enzymes. Moreover, the molecular docking studies were carried out to explore the interactive behavior of the compounds within the active pocket of enzymes. Furthermore, the derivatives (3a-h) were evaluated for their anticancer potential against HeLa cancer cell lines. Most potent inhibition was observed by compound 3b.     

Synthesis and biological evaluation of Schizandrin derivatives as tubulin polymerization inhibitors

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC₅₀ values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G₀/G₁ phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.     

Novel berberine-based derivatives with potent hypoglycemic activity

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.     

Design,synthesis and evaluation of 2-(indolylmethylidene)-2,3-dihydro-1-benzofuran-3-one and 2-(indolyl)-4H-chromen-4-one derivatives as novel monoamine oxidases inhibitors

A series of 2-(indolylmethylidene)-2,3-dihydro-1-benzofuran-3-ones (aurone-indole hybrids) and 2-(indolyl)-4H-chromen-4-ones (flavone-indole hybrids) were designed, synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 5b and 11b showed potent inhibitory activities against MAO-A, comparable to that of pargyline used as a positive control, and most of the compounds, except for 2a and 10b, showed potent inhibitory activities against MAO-B. Compound 9a was the most potent and highly selective inhibitor of MAO-B (IC₅₀ value for MAO-B: 0.0026 μM, and MAO-A: >100 μM). Comparison of the inhibitory activities of 1a vs. 9a vs. 13a and 1b vs. 7b vs. 11b suggested that methoxy substitution at R¹ on the A-rings of flavonoids increases MAO-A inhibition whereas methoxy substitution at R² increased MAO-B inhibition. Comparison of 4a vs. 10a, 6a vs. 11a, 3b vs. 8b and 4b vs. 9b showed incremental increases in MAO-B inhibitory activity by R² substitution on the A ring. Comparison of the MAO-B inhibitory effects of the flavone-indole hybrids and aurone-indole hybrids showed that most of the aurone-indole hybrids were stronger inhibitors than the corresponding flavone-indole hybrids. Molecular docking analysis of compounds 1a and 9a with MAO-B further supported the above structural effects of these compounds on MAO-B inhibitory activity.This is the first report identifying aurone-indole hybrids as potent MAO-B inhibitors. The results reported here suggest that 2-(1H-indol-1-ylmethylene)-6-methoxy-3(2H)-benzofuranone (9a) might be a useful lead for the design and development of novel MAO-B inhibitors     

Design,synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC₅₀ values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.     

Novel 5-(benzyloxy)pyridin-2(1H)-one derivatives as potent c-Met inhibitors

A series of novel 5-(benzyloxy)pyridin-2(1H)-ones were designed, synthesized and biologically evaluated for c-Met inhibition. Various amides and benzoimidazoles at C-3 position were investigated. A potent compound 12b with a c-Met IC₅₀ of 12 nM was identified. This compound exhibited potent inhibition of EBC-1 cell associated with c-Met constitutive activation and showed high selectivity for c-Met than other tested 11 kinases. The binding model 12b with c-Met was disclosed by docking analysis.