Semisynthetic Analogs of the Antibiotic Fidaxomicin – Design, Synthesis, and Biological Evaluation

<p>The glycoslated macrocyclic antibiotic fidaxomicin (1, tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Main limitations of the compound include low water solubility, which impacts further clinical use. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities</p>

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Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b01750 ◽

2019 ◽

Vol 62 (6) ◽

pp. 2950-2973 ◽

Cited By ~ 8

Author(s):

Chenghui Shi ◽

Yinyong Zhang ◽

Ting Wang ◽

Wenchao Lu ◽

Shuhua Zhang ◽

...

Keyword(s):

Dna Gyrase ◽

Multidrug Resistant ◽

Biological Evaluation ◽

Gram Positive ◽

Design Synthesis ◽

Gram Positive Bacteria ◽

Synthesis And Biological Evaluation

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Design, Synthesis and Biological Evaluation of Antagonists of LHRH by Criteria of Potency, Safety and Solubility

Zeitschrift für Naturforschung B ◽

10.1515/znb-1991-0917 ◽

1991 ◽

Vol 46 (9) ◽

pp. 1231-1236 ◽

Cited By ~ 4

Author(s):

Anders Ljungqvist ◽

Dong-Mei Feng ◽

Cyril Bowers ◽

William A. Hook ◽

Karl Folkers

Keyword(s):

Histamine Release ◽

Water Solubility ◽

Parent Compound ◽

Biological Evaluation ◽

Design Synthesis ◽

The Third ◽

Hydrophilic Residues ◽

Antiovulatory Activity ◽

Synthesis And Biological Evaluation

Some analogs of Antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. In position 1, D-3-Qal has been incorporated in four peptides and D-3-Pal in one peptide. In positions 5 and 6, D and L-3-Pal, PzAla and (DSer)Lys have been tried. In one peptide, D—(AcDSer)Lys was substituted in position 6.Most of the new analogs had lower AOA (antiovulatory activity) than the parent compounds but three potent analogs were identified. The first one, [N — Ac— D — 3-Qal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D — PicLys6,ILys8,D — Ala10]— LHRH, had 55% AOA at 0.25 μg and 100% at 0.5 μg. Its ED50 for in vitro histamine release was 171 ± 17 μg/ml which is an increase from 49±4.8 μg/ml for the parent compound with N—Ac-D-2-Nal [1].The second analog, [N — Ac— D — 2-Nal1,DpClPhe2,D — 3-Pal3,PicLys5,D — (DSer)Lys6,ILys8,D—Ala10] — LHRH, had 69% AOA at 0.25 μg and 95% at 0.5 μg. This analog released somewhat more histamine than the parent analog featuring D-PicLys6, the ED50 being 18 μg/ml compared to 93 ± 11 for the parent analog.The third analog is:[N — Ac— D— 2-Nal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D—PzAla6,ILys8,DAla1]— LHRH. The AOA for this analog was 63% at 0.25 μg and the ED50 for histamine release 88±6.4 μg/ml.

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Design, synthesis, and biological evaluation of quinazoline derivatives containing piperazine moieties as antitumor agents

Journal of Chemical Research ◽

10.1177/1747519820910384 ◽

2020 ◽

Vol 44 (9-10) ◽

pp. 536-542

Author(s):

Wen Li ◽

Shu-Yi Chen ◽

Wei-Nan Hu ◽

Mei Zhu ◽

Jia-Min Liu ◽

...

Keyword(s):

Biological Activity ◽

Antitumor Agents ◽

Biological Evaluation ◽

Substitution Reactions ◽

Migration Ability ◽

Design Synthesis ◽

Excellent Activity ◽

Quinazoline Derivatives ◽

Synthesis And Biological Evaluation ◽

Antiproliferative Activities

A series of novel quinazoline derivatives containing piperazine analogs are synthesized via substitution reactions with 6,7-disubstituted 4-chloroquinazoline and benzyl piperazine (amido piperazine). Potent antiproliferative activities are observed against A549, HepG2, K562, and PC-3 with N-(3-chlorophenyl)-2-(4-(7-methoxy-6-(3-morpholino-propoxy)quinazoline-4-yl)piperazine-1-yl)acetamidename C9 showing excellent activity. This active derivative was screened for cell migration ability, proliferation effects, and apoptosis against A549 and PC-3 cells, with the result showing biological activity almost equal to that of the control gefitinib.

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