Synthesis and Antitumor Activity of C-3 Arylidene Thiazolotriazolone of Ofloxacin Derivatives / 中国药学杂志

OBJECTIVE: To discover an efficient strategy for a conversion of the antibacterial activity into an antitumor activity. METHODS: Pharmacophore and scaffold hopping-based rational drug design principles, the title fluoroquinolone C-3 thiazolotriazole unsaturated ketones (6a-6l) were designed and synthesized with a S-triazole ring and α,β-unsaturated ketone, respectively, as an isostere and fused modified group from ofloxacin (1), and their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity against the tested tumor cell lines was evaluated by a MTT assay. RESULTS: Twelve new title compounds were synthesized, and exhibited more significant potency than parent 1. The title compounds with fluorophenyl or O-methoxyphenyl displayed comparable activity to comparasion doxorubicin. CONCLUSION: A fused heterocyclic unsaturated ketone skeleton as an isostere of the C-3 carboxylic acid group are shown to be an alternative route for further design of lead antitumor fluoroquinolone.

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 3-(5-benzylidenethuzolo-triazlone)fluoroquinolones / 中国药科大学学报

@#To discover an efficient approach for the conversion of antibacterial fluoroquinolones into an antitumor activity, a fused heterocycle ring core, thiazolo［3, 2-b］［1, 2, 4］triazol-5-one was used as an isostere and further modified with an arylidene group. Then, 12 novel C-3 fused heterocyclic unsaturated ketones, 1- ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-［6-arylidene-thiazolo［3, 2-b］［1, 2, 4］triazol-5(6H)-one-3-yl］- quinolon-4(1H)-ones(6a-6l), were designed and synthesized from pefloxacin(1). The structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against SMMC-7721, Capan-1 and HL60 cell lines was evaluated. The preliminary pharmacological results demonstrated that the title compounds exhibited more significantly antiproliferative activity than the parent 1. The compounds with fluorophenyl or o-methoxyphenyl showed comparable activity to the comparasion doxorubicin. Thus, it appears to be an alternative route for a fused heterocyclic unsaturated ketone as an isostere of the C-3 carboxylic group to improve the antitumor activity.

Synthesis and Antitumor Activity Evaluation of C-3 (Rhodanine Unsaturated Ketone) Amides as Ofloxacin Derivatives / 中国药学杂志

OBJECTIVE: To explore an efficient strategy for converting the antibacterial activity of fluoroquinolones to antitumor activity. METHODS: An amide group as an isostere modified by rhodanine unsaturated ketone moiety corresponding to the C-3 carboxylic acid group resulted in 12 new title C-3 (5-arylidene-2-thioxo-1, 3-thiozolidin-2, 4 -dione-3-yl) amides (6a - 6l) from ofloxacin 1. Their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested cell lines was evaluated by MTT assay. RESULTS: Twelve new title compounds were synthesized from ofloxacin and exhibited significantly higher potency than the parent compound ofloxacin. CONCLUSION: Using a rhodanine unsaturated ketone hybrided amide group as the C-3 bioisostere is favorable to improve antitumor activity.

3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors

Dengue is a severe mosquito-borne viral infection causing half a million deaths annually. Dengue virus NS2B/NS3 protease is a validated target for anti-dengue drug design. A series of hitherto unreported 3,5-bis(arylidene)-4-piperidones analogues-were synthesized and screenedagainst DENV2 NS2B/NS3 protease to elucidate their binding mechanism and orientation around the active sites. Results were validated through anDENV2 NS2B/NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Nitro derivatives of 3,5-bis(arylidene)-4-piperidones (and) emerged as promising lead molecules for novel protease inhibitors with an ICof 15.22 and 16.23 µmol/L, respectively, compared to the standard, panduratin A, having ICof 57.28 µmol/L.

Synthesis and antitumor activity of pefloxacin C-3 (rhodanine unsaturated ketone) amide derivatives / 中国药科大学学报

To explore a new strategy for the transformation of antibacterial activity of fluoroquinolone into antitumor activity,twelve new title compounds,1-ethyl-6-fluoro-7-(4-methyl-pipreazin-1-yl)-quinolin-4-one-3-carboxylicacid (5-arylidene-2-thioxo-1,3-thiozolidin-2,4-dione-3-yl) amides (6a-61),were designed and synthesized with an amide group and a rhodanine unsaturated ketone moiety as an isostere and modified group,respectively,from pefloxacin (1).Their structures were characterized by elemental analysis and spectral data.The in vitro antitumor activity of the title compounds against Hep-3B,Capan-1 and L1210 cell lines exhibited more significant potency than pefloxacin.The compounds with aromatic heterocyclic or flurophenyl displayed comparable activity to the comparasion doxorubicin.Thus,rhodanine unsaturated ketone hybrided amide group as an isostere of the C-3 carboxylic acid group appears to be an alternative route for further design of antitumor fluoroquinolone.