Application of bioisostere-bicyclo [1.1.1] pentane (BCP) in drug design / 中国药科大学学报

@#With the development of medicinal and organic chemistry, more and more classical and non-classical bioisosteres are used in the design of novel drugs.Bicyclo[1.1.1] pentane (BCP), as a bioisostere of benzene, t-butyl and alkyne moieties,has recently received extensive attention from medicinal and organic chemists.This paper briefly reviews its application in drug design to provide reference for drug discovery researchers.

Application of bioisostere difluoromethyl in medicinal chemistry and the research progress in its synthetic methods / 药学学报

Bioisosterism is one of the most common strategies in drug structure optimization. With the development of medicinal and organic chemistry, more and more classic and non-classical bioisosteres are used in the design of novel drugs. In recent years, fluorinated groups as a bioisostere have been paid more and more attention by pharmaceutical chemists. This paper briefly reviews the physicochemical properties, chemical preparation methods of difluoromethyl (CF2H) group, and its application in drug design to provide references for drug discovery researchers.

Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin / 药学学报

To expand an efficient strategy for the conversion of antibacterial activity of fluoroquinolones into an antitumor activity, sixteen new compounds, 1-cyclopropyl-6- fluoro-7-(4-methyl-piperazin-1-yl)-3-(5-arylidene-thiazol-4(5H)-one-2-yl)-quinolon-4(1H)-ones (7a-7p), were designed and synthesized with a thiazolone ring and an arylidene moiety as an isostere and modified group, respectively, from ciprofloxacin. Their structures were characterized by elemental analysis and spectral data. The in vitro antitumor activity of the synthesized compounds were measured using Hep-3B, Capan-1 and HL60 cell lines and were found to be more potent than ciprofloxacin. Meanwhile, the SAR revealed that the halogenated phenyl compounds such as fluorophenyl (7h, 7i), chlorophenyl (7j, 7k) or bromophenyl compounds (7l, 7m), and aromatic heterocyclic substitution such as furyl (6n) or pyridyl compounds (6o, 6p) displayed better activity than the control compounds, especially the IC50 values of pyridyl compounds 6o and 6p against Capan-1 cell growth was comparable to doxorubicin. Thus, an arylidene-modified thiazolone scaffold as the replacement of the C-3 carboxylic acid group appears to be an alternative route for an improved antitumor activity of fluoroquinolones.

Synthesis and antitumor activity of pefloxacin C-3 methylene rhodanine devatives / 中国药科大学学报

@#To further explore an efficient strategy for the construction of antitumor fluoroquinolone molecules from antibacterial fluoroquinolone drugs, twelve new title compounds, 1-ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(3-substituted-rhodanin-5-ylidene)methyl-quinolon-4(1H)-ones(6a-6l), was designed and synthesized with α, β-unsaturated ketone scaffold and a rhodanine ring as an isostere and fused modified group, respectively, from pefloxacin(1), and their structures were characterized by elemental analysis and spectral data. The in vitro anti-cell proliferative activity of the title compounds against the tested A549, Hep-3B and HL60 cancer cells exhibited more significant potency than parent 1. In particular, halogenated phenyl title compounds(6d, 6e, 6f)displayed a comparable activity to comparison doxorubicin against A549 cells and low cytotoxicity against normal Vero cells. Thus, a methylene rhodanine scaffold as a bioisostere of the C-3 carboxylic acid group have shown to be beneficial to improving the antitumor activity.

Synthesis and antitumor activity of fluoroquinolone C-3 fused heterocyclic thiazolo3, 2-b 1, 2, 4triazole derivatives (VI) / 中国药学杂志

OBJECTIVE: To discover an efficient strategy for conversion of the antibacterial activity of fluoroquinolone drugs to antitumor activity. METHODS: Novel title fused heterocyclic C-3 thiazolo[3,2-6] [1,2,4] triazole derivatives(5,6) were designed by using a s-triazole ring as the bioisostere and modifying it by a fused condensation-cyclization reaction. The structures were validated by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested tumor cell lines was evaluated by MTT assay. RESULTS: Twelve title compounds were synthesized from ofloxacin and exhibited more significant antiproliferative activity than both of parent ofloxacin 1 and the corresponding intermediate sulfide ketones 5, but displayed a slightly weaker activity than the corresponding sulfide ketone thiosemi-carbazones 6. CONCLUSION: An efficient structure modification strategy for the fused heterocyclic core of thiazolotriazole used as the C-3 bioisostere warrants further development.

Synthesis and antitumor activity of fluoroquinolon-3-yl s-triazole sulfanylacetylhydrazones and s-triazole hydrazone derivatives (V) / 中国药学杂志

OBJECTIVE: To explore an efficient modification strategy for conversion of antibacterial fluoroquinolones to antitumor ones. METHODS: An azole heterocyclic ring, s-triazole, as a bioisotere of the C-3 carboxylic acid for ofloxacin(1), functional acyl-hydrazones and hydrazones, was used as the modified side-chain for the C-3 bioisotere, then the C-3 s-triazole acylhydrazones and s-triazole hydrazone derivatives were designed and their in vitro antitumor activity was evaluated by MTT assay. RESULTS: Fourteen target compounds were synthesized, and they exhibited stronger antitumor activity than the parent ofloxacin. And most importantly, hydrazone derivatives had higher activity than their corresponding acylhydrazone compounds. CONCLUSION: s-Triazole-hydrazone moiety is warranted special attention as an efficient bioisosteric replacement of the C-3 carboxylic acid for further development of antitumor fluoroquinolone lead compounds.

Synthesis and antitumor activity fluoroquinolon-3-yloxadiazole sulfanylacetylhydrazone derivatives / 中国药学杂志

OBJECTIVE: To explore an efficient modification strategy for a bioisotere antibacterial fluoroquinolon-3-yl carboxylic acid group for developing compounds with improved antitumor activity. METHODS: Novel title 2-(fluoroquinolon-3-yl)-oxadiazole-5-sulfanylacetylhydrazone derivatives were designed on the basis the pharmacophore skeleton transition principle, and the in vitro activity the title compounds was evaluated by MTT assay. RESULTS: Fourteen target compounds were synthesized from ofloxacin and exhibited more potent antitumor activity than the parent compound, especially the compounds with a carboxylic group-substitued phenyl ring as a modified group around the bioisostere, which had comparable activity to doxorubicin. CONCLUSION: A hydrazone with electron-withdrawing substituents warrants further development as the modified side-chain for the C-3 bioisostere.

Synthesis and antitumor activity of fluoroquinolone C-3 heterocycles-oxadiazole derivatives (II) / 中国药学杂志

OBJECTIVE: To discover an efficient route for the conversion of an antibacterial fluoroquinolone to an antitumor one. METHODS: Cyclo-condensation of ofloxacin hydrazide 2 with aromatic carboxylic acids in POCl3 gave the corresponding oxadiazole derivatives 3a-3j, and their antitumor activity was evaluated by MTT assay. RESULTS: Ten title compunds were synthesized and showed potential antitumor activity. CONCLUSION: Heterocycles as isosteric replacement of carboxyl are warrant further development.