Design,synthesis and antibacterial activity of novel andrographolide derivatives

A series of andrographolide derivatives were synthesized through a facile condensation reaction with different carboxylic acids. The new compounds were characterized and screened for their antibacterial activities. A number of the new compounds significantly reduced bacterial quorum sensing virulence factors production in Pseudomonas aeruginosa, essential for pathogenesis. Compound 11b showed the best activity among all the new compounds.     

Design, synthesis, and evaluation of peptides with estrogen-like activity

Currently used antiestrogenic drugs against hormone-dependent breast cancer, and estrogenic drugs used in treatment of osteoporosis, are associated with risk factors. Therefore, there is a strong need to develop selective estrogen receptor modulators with better tissue selectivity. In a recent study (Peptides, 2002, Vol. 3, 573-580), we used a monoclonal antibody to estradiol (mAb-E2) to screen a phage-display peptide library. We identified a 15-mer peptide (peptide H5) that recognizes mAb-E2 (IC(50) 1 microM) and estrogen receptor (ER)alpha (IC(50) 500 microM) but not ERbeta, and displays estrogen-like activity in vitro and in vivo. In this study, we designed and prepared peptides based on peptide H5, which possess improved estrogenic activity, by evaluating their binding to mAb-E2 and to ERs. Initially, we determined the minimal binding sequence of peptide H5 capable of binding mAb-E2 and ER. Subsequently, systematic single-residue replacements of the minimal sequence, followed by multiple-residue replacements, yielded hexa- and heptapeptides with increased affinities to mAb-E2 and to ER. The most promising peptides, VSWFFE (EMP-1) and VSWFFED (EMP-2) (EMP: estrogen-mimetic peptide), bind mAb-E2 with high affinity (IC(50) of 6 and 30 nM, respectively), recognize ERs with increased affinity (IC(50) of 100 microM for ERalpha, and 100-250 microM for ERbeta), and possess estrogenic activity in vivo. The short peptides described in this study may be used as potential lead compounds for developing new ER ligands.     

Design,synthesis, and activity evaluation of novel erythropoietin mimetic peptides

The approval of the erythropoietin (EPO) mimetic peptide drug peginesatide in 2012 was a breakthrough for the treatment of secondary anemia. However, due to severe allergic reactions, peginesatide was recalled a year later. In this study, 12 novel peptides were designed and synthesized by substituting specific amino acids of the monomeric peptide in peginesatide, with the aim of obtaining new EPO mimetic peptides with higher activities and lower side effects than the parent compound. Their cell proliferation activities were evaluated, and the structure-activity relationships were analyzed. Five compounds had equal cell proliferation activity to the control peptide. Among them, one compound showed a higher in vivo activity than the control peptide, with no obvious side effects.     

Design,synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids

In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l were designed and synthesized. The in vitro antibacterial activity against a panel of clinically important Gram-positive and Gram-negative bacteria including drug-resistant pathogens was also evaluated. All hybrids showed considerable activity against the tested pathogens with MIC values of ≤0.03 to 128 μg/mL, and some of them such as hybrids 7e, 7g and 7j were comparable to or better than the parent moxifloxacin (MIC: ≤0.03–8 μg/mL). Moreover, hybrids 7e, 7g and 7j also demonstrated low cytotoxicity towards CHO cells. However, the in vivo pharmacokinetic profiles of these three hybrids were generally far inferior to the parent moxifloxacin. The structure-activity relationship and structure-cytotoxicity relationship were also studied and discussed which may help with the identification of new chemical entities as potent antibacterial agents.     

Design, synthesis and antibacterial activity studies of model peptidess of proline/arginine-rich region in bactenecin7

Bactenecin 7 (Bac7), a cationic antibacterial peptide, contains a repeating region of Xaa-Pro-Arg-Pro (Xaa = hydrophobic residue). To investigate the structure and property of a Pro/Arg-rich region, e synthesized a series of peptides, Xaa-Pro-Arg-Pro (Xaa = Gly, Arg, Leu, Ile, and Phe) as models and characterized . The conformational preferences of these peptides in water and trifluoroethanol were examined by circular dichroism. The results suggest the presence of largely poly(Pro)-II helical conformation in aqueous and trifluoroethanol solutions. Their antibacterial activity against gram-negative bacteria such as Escherichia coli, Klebsiella Pneumoniae, Pseudomonas aeruginosa, and Escherichia coliHB101, and gram-positive bacteria such as Staphylococcus aureus were measured at various peptide concentrations. Two of our synthetic tetrapeptide fragments containing Gly and Arg were efficiently killed with gram-positive bacteria, Staphylococcus aureus, at the concentration level of 200 microg/mL.     

Design, synthesis and antibacterial activity of novel 1,3-thiazolidine pyrimidine nucleoside analogues

The synthesis of a new class of 1,3-thiazolidine nucleoside analogues in which furanose oxygen atom was replaced with nitrogen atom and 2'-carbon atom with sulfur atom is described. N-tert-butoxycarbonyl-2-acyloxy-4-trityloxymethyl-1,3-thiazolidine was coupled with the pyrimidine bases like uracil, thymine, etc. in the presence of lewis acids stannic chloride or trimethyl silyl triflate following Vorbruggen procedure. The antibacterial activity of the novel 1,3-thiazolidine pyrimidine nucleoside analogues is highlighted. All compounds (7a-e) with free NH group in the pyrimidine moiety showed significant biological activity against all the standard strains used and in that compounds 7d and 7e showed significant activity against 14 human pathogens tested.     

Structure-activity relationships of cecropin-like peptides and their interactions with phospholipid membrane

Cecropin A and papiliocin are novel 37-residue cecropin-like antimicrobial peptides isolated from insect. We have confirmed that papiliocin possess high bacterial cell selectivity and has an α-helical structure from Lys³ to Lys²¹ and from Ala²⁵ to Val³⁵, linked by a hinge region. In this study, we demonstrated that both peptides showed high antimicrobial activities against multi-drug resistant Gram negative bacteria as well as fungi. Interactions between these cecropin-like peptides and phospholipid membrane were studied using CD, dye leakage experiments, and NMR experiments, showing that both peptides have strong permeabilizing activities against bacterial cell membranes and fungal membranes as well as Trp² and Phe⁵ at the N-terminal helix play an important role in attracting cecropin-like peptides to the negatively charged bacterial cell membrane. Cecropin-like peptides can be potent peptide antibiotics against multi-drug resistant Gram negative bacteria and fungi. [BMB Reports 2013; 46(5): 282-287]     

Induction, selection and antibacterial activity of the antibacterial peptides from lepldopteran insect cultured cell lines

We induced 3 cell lines that were in vitro cultured from Lepidoptera with heat inactivated Escherichia coil DH5α to stimulate the antibacterial peptide followed by antibacterial activity assay,induction dynamic research and Tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Tricine SDS-PAGE) experiment.The antibacterial activity of the induced BTI-Tn-5B1 cell line was the highest,and the antibacterial activity increased gradually to the highest level in 16 hours after stimulation.A new antibacterial peptide with a molecular weight of about 8000 Da was preferentially induced in Trichoplusia ni BTI-Tn-5B1 ceils in 16 hours after stimulation.Antibacterial activity assays indicated that it had inhibition against Staphylococcus aureus,Escherichia coli K12D31 and Salmonella derby.It has especially strong inhibition against Gram-negative bacteria such as Escherichia coli KI2D31 and Salmonella derby.     

Induction, selection and antibacterial activity of the antibacterial peptides from lepidopteran insect cultured cell lines

We induced 3 cell lines that were in vitro cultured from Lepidoptera with heat inactivated Escherichia coli DH_5α to stimulate the antibacterial peptide followed by antibacterial activity assay, induction dynamic research and Tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Tricine SDS-PAGE) experiment. The antibacterial activity of the induced BTI-Tn-5B1 cell line was the highest, and the antibacterial activity increased gradually to the highest level in 16 hours after stimulation. A new antibacterial peptide with a molecular weight of about 8000 Da was preferentially induced in Trichoplusia ni BTI-Tn-5B1 cells in 16 hours after stimulation. Antibacterial activity assays indicated that it had inhibition against Staphylococcus aureus, Escherichia coli K₁₂D₃₁ and Salmonella derby. It has especially strong inhibition against Gram-negative bacteria such as Escherichia coli K₁₂D₃₁ and Salmonella derby. __________ Translated from Journal of Central China Normal University (Natural Sciences), 2006, 40(2): 240–243 [译自: 华中师范大学学报 (自然科学版]     

Design,synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors

Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli β-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram-positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56–6.25 μg/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC₅₀ of 5.3 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein.     

Design,synthesis and antibacterial evaluation of honokiol derivatives

Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1 × MIC and 4 × MIC.     

Design,synthesis, antibacterial activity and physicochemical parameters of novel N-4-piperazinyl derivatives of norfloxacin

We report herein the synthesis of some N-Mannich bases in addition to different N-4 substituents of norfloxacin. The antibacterial activities of the newly synthesized compounds were evaluated and correlated with their physicochemical properties. Results revealed that some of the tested compounds exhibited better inhibitory activities than the reference antibiotic norfloxacin against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus strains. Correlation results showed that there is no single physicochemical parameter that can determine the effect of N-4 piperazinyl group on the activity of these fluoroquinolones, where lipophilicity, molecular mass and electronic factors may influence the activity.     

Lipase-catalyzed synthesis and antibacterial activity of N-vanillylnonanamide

N-vanillylnonanamide (VAN) was successfully synthesized from vanillylamine hydrochloride by enzymatic catalysis in supercritical carbon dioxide (SC–CO₂). Five commercial lipases, Novozyme 435, Lipozyme IM, Amano PS, Amano G and Sigma Candida cylindracea type VII, as biocatalysts for VAN synthesis were compared. Lipozyme IM exhibited best yields of tested lipases. Various parameters such as time, temperature, pressure and vanillylamine hydrochloride/nonanoic anhydride ratio that influenced the reaction were investigated. Nonanoic anhydride showed the best acyl donor of the employed substrates. An amidation yield of 40% was obtained when nonanoic anhydride and Lipozyme IM were used at 170 bar and 50 °C for 23 h in SC–CO₂. Besides, addition of 2 mM divalent salts (CuCl₂ and ZnCl₂) significantly increased 11–23% yield of the VAN. The enzyme operational stability suggested that Lipozyme IM maintained over 50 °C of the initial activity for the synthesis of VAN after reuse for 69 h. Furthermore, in vitro, VAN behaved as a potential antibacterial against Escherichia coli.     

Design,synthesis and biological evaluation of potential antibacterial butyrolactones

Novel butyrolactone analogues were designed and synthesized based on the known lichen antibacterial compounds, lichesterinic acids (B-10 and B-11), by substituting different functional groups on the butyrolactone ring trying to enhance its activity. All synthesized butyrolactone analogues were evaluated for their in vitro antibacterial activity against Streptococcus gordonii. Among the derivatives, B-12 and B-13 had the lowest MIC of 9.38 μg/mL where they have shown to be stronger bactericidals, by 2–3 times, than the reference antibiotic, doxycycline. These two compounds were then checked for their cytotoxicity against human gingival epithelial cell lines, Ca9–22, and macrophages, THP-1, by MTT and LDH assays which confirmed their safety against the tested cell lines. A preliminary study of the structure–activity relationships unveiled that the functional groups at the C₄ position had an important influence on the antibacterial activity. An optimum length of the alkyl chain at the C₅ position registered the best antibacterial inhibitory activity however as its length increased the bactericidal effect increased as well. This efficiency was attained by a carboxyl group substitution at the C₄ position indicating the important dual role contributed by these two substituents which might be involved in their mechanism of action.     

Design,synthesis and antibacterial evaluation of novel AHL analogues

Two series of novel AHL analogues were designed, synthesized and evaluated for antibacterial activity under cell membrane conditions in vitro. Analogues 4a–c and 4g–m presented potent activity against Gram-positive bacteria. Especially the analogue 4l exerted the most potent inhibition against Bacillus subtilis with MIC₅₀ value of 1.443 μg/ml. To our surprise, analogues 6a–c and 6g showed weak inhibition against Gram-negative bacteria with MIC₅₀ values ranging from 17.589 to 67.840 μg/ml. This was the first report about synthesis and antibacterial evaluation in vitro of AHL analogues containing dithioester linkage.     

Design, synthesis and catalytic activity of a serine protease synthetic model

Summary The design, synthesis and catalytic properties of a cyclic branched peptide carrier that possesses the catalytic triad residues of the serine proteases is reported. The synthesis of the peptide model was totally completed on solid support using three different orthogonal amino protecting groups. Hydrolytic activity measurements against Suc-Ala-Ala-Ala-pNA substrate showed that it is hydrolysed by the peptide model to a small extent. Despite this small hydrolytic activity, it is the first time, to our knowledge, that hydrolysis of such a substrate is reported by an enzyme model compound. Contrary, this enzyme model peptide showed considerable activity against the Boc-Ala-pNP substrate (k _cat =0.414 min⁻¹ andK _m =0.228 mm). These results suggest that the designed carrier brings in appropriate contact the catalytic triad residues (Ser, His, Asp) resulting in the obtained hydrolytic activity.     

Design, synthesis and catalytic activity of a serine protease synthetic model

The design, synthesis and catalytic properties of acyclic branched peptide carrier that possesses thecatalytic triad residues of the serine proteases isreported. The synthesis of the peptide model wastotally completed on solid support using threedifferent orthogonal amino protecting groups.Hydrolytic activity measurements againstSuc-Ala-Ala-Ala-pNA substrate showed that it ishydrolysed by the peptide model to a small extent.Despite this small hydrolytic activity, it is thefirst time, to our knowledge, that hydrolysis of such a substrate is reported by an enzyme model compound.Contrary, this enzyme model peptide showedconsiderable activity against the Boc-Ala-pNPsubstrate (k_cat = 0.414 min^–1 and K_m = 0.228 mm). These results suggest that thedesigned carrier brings in appropriate contact thecatalytic triad residues (Ser, His, Asp) resulting inthe obtained hydrolytic activity.     

Dimeric unnatural polyproline-rich peptides with enhanced antibacterial activity

We report a dimerization strategy to enhance the antibacterial potency of an otherwise weak cationic amphiphilic polyproline helical (CAPH) peptide. Overall, the dimeric CAPHs were more active against Escherichia coli and Staphylococcus aureus than the monomeric counterpart, reaching up to a 60-fold increase in potency. At their minimum inhibitory concentration (MIC), the dimeric peptides demonstrated no hemolytic activity or bacterial membrane disruption as monitored by β-galactosidase release in E. coli. At higher concentrations the dimeric agents were found to induce β-galactosidase release, but maintained negligible hemolytic activity, pointing to a potential shift in the mechanism of action at higher concentrations. Thus, discontinuous dimerization of an unnatural proline-rich peptide was a successful strategy to create potent de novo antibacterial peptides without membrane lysis.