Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Design,synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity

A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC₅₀ (FXa) value of 0.14 μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.     

Design,synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor

Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC₅₀ value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure–activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2′-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.     

Design,synthesis and antistaphylococcal activity of marine pyrrole alkaloid derivatives

Abstract

A novel set of 16 hybrids of bromopyrrole alkaloids with aroyl hydrazone were designed, synthesized and evaluated for antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43866), methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 35556) and Staphylococcus epidermidis (SE, S. epidermidis ATCC 35984). Of the 16 tested hybrids, 14 exhibited equal or superior antibiofilm activity against MSSA and MRSA relative to standard vancomycin. Compound 4m showed highest potency with antibiofilm activity of 0.39?µg/mL and 0.78?µg/mL against MSSA and MRSA, respectively. Thus, this compound could act as a potential lead for further development of new antistaphylococcal drugs.     

Design,synthesis, and biological activity evaluation of a series of pleuromutilin derivatives with novel C14 side chains

In this work, according to the ‘me-too me-better’ design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.     

Design,synthesis, biological activities,and dynamic simulation study of novel thiourea derivatives with gibberellin activity towards Arabidopsis thaliana

Computer-aided drug design has advanced by leaps and bounds, and has been widely used in various fields, and especially in the field of drug discovery. Although the crystal structure of the gibberellin (GA) receptor GID1A had been reported in previous studies, there is still a lack of designs of gibberellin functional analogue based GID1A. In the present study, a series of 30 thiourea derivatives were designed, synthesized and biologically assayed. The results suggested that the synthetic compounds had good GA-like activities. Furthermore, the structure-activity relationship of the synthetic compounds was discussed, and the dynamic simulation and docking study revealed the binding properties of the GID1A receptor and compounds Y1, Y11, and Y21.     

Design,synthesis and biological evaluation of novel L-isoserine tripeptide derivatives as aminopeptidase N inhibitors

Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC₅₀?=?2.51?±?0.2 µM) showed similar inhibitory effect compared with control compound Bestatin (IC₅₀?=?6.25?±?0.4 µM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future.     

Design and synthesis of 21-alkynylaryl pregnenolone derivatives and evaluation of their anticancer activity

A series of novel C21-alkynylaryl derivatives of pregnenolone were synthesized and screened for anticancer activity against a panel of seven human cancer cell lines (LNCaP, A549, MCF7, HeLa, A431, HepG2, HT29). The data revealed that these compounds can be potential antitumour agents against the specific cell models. Compound 6f bearing a 2-trifluoromethylphenyl group displayed improved cytotoxicity towards all cancer cell lines used. A431 cells were the most sensitive with derivatives 6e–6h bearing electron withdrawing substituents exhibiting high potency with IC₅₀ values ranging between 2.18 and 0.54 μM and drastic inhibition of the prosurvival PI3K-Akt/PKB pathway.     

Design,synthesis and anti-influenza A virus activity of novel 2,4-disubstituted quinazoline derivatives

Four 2,4-disubstituted quinazoline series containing various amide moieties were designed and synthesized as new anti-influenza A virus agents using the strategies of bio-isosterism and scaffold hopping. Many of them exhibit potent in vitro anti-influenza A virus activity and low cytotoxicity (CC₅₀: >100 μM). Particularly, compounds 10a5 and 17a show better activity (IC₅₀: 3.70–4.19 μM) and higher selective index (SI: >27.03, >23.87, respectively) against influenza A/WSN/33 virus (H1N1), opening a new direction for quinazoline derivatives in anti-influenza A virus field.     

Design,synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.     

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.     

Design,synthesis and biological evaluation of novel zanamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q²?=?0.728 and r²?=?0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q²?=?0.750 and r²?=?0.981, respectively. The built 3D-QSAR models show significant statistical quality and excellent predictive ability. Seven new NA inhibitors were designed and predicted. 20?ns of MD simulations were carried out and their binding free energies were calculated. Two designed compounds were selected to be synthesized and biologically evaluated by NA inhibition and virus inhibition assays. One compound (IC₅₀?=?0.670?µM, SI?>?149) exhibits excellent antiviral activity against A/WSN/33 H1N1, which is superior to the reference drug zanamivir (IC₅₀?=?0.873?µM, SI?>?115). The theoretical and experimental results may provide reference for development of new anti-influenza drugs.     

Design,synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors

STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC₅₀ values as low as 7.71 μM and 1.38 μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC₅₀ value of 9.61 μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.     

New 1,4-di-N-oxide-quinoxaline-2-ylmethylene isonicotinic acid hydrazide derivatives as anti-Mycobacterium tuberculosis agents

The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research.     

Design,synthesis and antifungal activity of amide and imine derivatives containing a kakuol moiety

In continuation of our program to discover new potential antifungal agents, a series of amide and imine derivatives containing a kakuol moiety were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against four plant pathogenic fungi, and structure–activity relationships (SAR) were derived. Compounds 7d, 7e, 7h, 7i and 7r showed obvious inhibitory activity against the corresponding tested fungi at 50 μg/mL. Especially, compounds 7e and 7r displayed more potent antifungal activity against B. cinerea than that of thiabendazole (a positive control). Moreover, compound 7e also exhibited good activity against A. alternata with EC₅₀ values of 11.0 µg/mL, and the value was slightly superior to that of thiabendazole (EC₅₀ = 14.9 µg/mL). SAR analysis showed that the ether group was a highly sensitive structural moiety to the activity and the type as well as position of substituents on benzene ring could make some effects on the activity.     

Design,synthesis, and biological evaluation of 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive candidates

A series of novel 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives were designed and synthesized to develop new angiotensin II subtype 2 (AT₂) receptor agonists as novel antihypertensive candidates. It was found that 14f (IC₅₀ = 0.4 nM) and 15e (IC₅₀ = 5.0 nM) displayed potent AT₂ receptor affinity and selectivity in binding assays. Biological evaluation in vivo suggested that 14f is obviously superior to that of reference drug losartan in RHRs, and meanwhile, 14f has no significant impact on heart rate. The interesting activities of these compounds may make them promising candidates as antihypertensive agents.     

结核分枝杆菌耐吡嗪酰胺分子机制研究

吡嗪酰胺(PZA)是结核病短程化疗中的一线抗结核药物,由吡嗪酰胺酶转换成为活性形式吡嗪酸而生效。吡嗪酰胺酶由pncA基因编码,pncA基因突变会导致该酶活性丧失,与PZA耐药性产生有关。为了进一步明确PZA耐药性产生的基因学基础和PZA耐药株的pncA基因突变率,对中国100株结核分枝杆菌临床分离株进行了DNA序列测定,其中85株为PZA耐药株,15株为PZA敏感株。PZA耐药株有27%(23/85)发生了pncA基因突变,从而导致吡嗪酰胺酶基本氨基酸序列的改变,突变分布在pncA基因开读框架17-546位的核苷酸。其中有一株突变位于pncA基因的调节区域-11位处。同时发现20%(3/15)pncA敏感株也发生了pncA基因突变。敏感株发生突变可能是由于PZA敏感性实验不准确或存在其它耐药机制。实验表明,pncA基因突变是PZA耐药的主要机制之一,中国PZA耐药临床分离株尚存在其它耐药分子机制。     

Naphthoquinone amino acid derivatives,synthesis and biological activity as proteasome inhibitors

The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC₅₀ values in the sub-µm range.     

Design,synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure

Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC₅₀ at 1.56 and 1.72?nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.