Synthesis, evaluation of anticancer activity and COMPARE analysis of N-bis(trifluoromethyl)alkyl-N’-substituted ureas with pharmacophoric moieties

Luzina, Elena L.; Popov, Anatoliy V.

doi:10.1016/j.ejmech.2012.03.026

Cited by 30 publications

(16 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The criteria evaluated for the Ro5 included the following: (1) molecular weight (MW) ≤ 500 g/mol, (2) CLogP ≤ 5, (3) number of H-bond donors ≤ 5, and (4) number of H-bond acceptors ≤ 10. In addition, the inhibitors were also in agreement with other key physiochemical parameters that are common amongst many successful drugs and were previously described by Luzina and Popov (49), as follows: (1) polar surface area (PSA) < 140 Å 2 , (2) molar refractivity (MR) in the range of 40 – 130 cm 3 /mol, and (3) the number of atoms in the molecule (including hydrogen atoms) in the range of 20 – 70 atoms. All of the inhibitors follow these criteria except for DBT-GlcN, which has a slightly higher PSA of 162.62 Å 2 .…”

Section: Resultssupporting

confidence: 81%

See 1 more Smart Citation

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

D'Antonio

Deinema

Kearns

et al. 2015

Molecular and Biochemical Parasitology

View full text Add to dashboard Cite

Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas’ disease. These glucose kinases phosphorylate D-glucose with co-substrate ATP and yields glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71 ± 0.05 μM. Also reported are two biologically active inhibitors against in vitro Trypanosoma cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08 ± 0.16 μM and 48.73 ± 0.69 μM, respectively. These compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provides a key starting point for further drug development with this class of compound.

show abstract

Section: Resultssupporting

confidence: 81%

“… a MW is molecular weight; MR is molar refractivity; and PSA is polar surface area. b Calculated using ChemDraw Ultra (version 12.0). c Lipinski’s Rule of Five; score is out of 4; refer to refs (47–49). …”

Section: Figurementioning

confidence: 99%

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

D'Antonio

Deinema

Kearns

et al. 2015

Molecular and Biochemical Parasitology

View full text Add to dashboard Cite

show abstract

“…The parameters were calculated with Chemicalize.org software and are presented in Table . All compounds 2 – 6 (except 4 e , which showed minimal aberration) are fully in agreement with Lipinski's and Gelovani's rules for prospective small‐molecule drugs (MW≤500, log P ≤5, number of H‐bond donors ≤5, number of H‐bond acceptors ≤10, TPSA<140 Å 2 , MR within the range of 40 and 130 cm 3 mol −1 , number of atoms 20–70) …”

Section: Resultssupporting

confidence: 79%

“…[59] All compounds 2-6 (except 4e,w hich showed minimal aberration) are fully in agreement with Lipinski's and Gelovani's rules for prospective small-molecule drugs (MW 500, log P 5, number of H-bondd onors 5, number of H-bond acceptors 10, TPSA < 140 2 ,M Rw ithin the range of 40 and 130 cm 3 mol À1 ,number of atoms 20-70). [60] Scheme1.Synthesis of PQ derivatives 2-6.…”

Section: Chemistrymentioning

confidence: 99%

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

et al. 2018

View full text Add to dashboard Cite

We report the synthesis of SAHAquines and related primaquine (PQ) derivatives. SAHAquines are novel hybrid compounds that combine moieties of suberoylanilide hydroxamic acid (SAHA), an anticancer agent with weak antiplasmodial activity, and PQ, an antimalarial drug with low antiproliferative activity. The preparation of SAHAquines is simple, cheap, and high yielding. It includes the following steps: coupling reaction between primaquine and a dicarboxylic acid monoester, hydrolysis, a new coupling reaction with O‐protected hydroxylamine, and deprotection. SAHAquines 5 a–d showed significant reduction in cell viability. Among the three human cancer cell lines (U2OS, HepG2, and MCF‐7), the most responsive were the MCF‐7 cells. The antibodies against acetylated histone H3K9/H3K14 in MCF‐7 cells revealed a significant enhancement following treatment with N‐hydroxy‐N′‐{4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}pentanediamide (5 b). Ethyl (2E)‐3‐({4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}carbamoyl)prop‐2‐enoate (2 b) and SAHAquines were the most active compounds against both the hepatic and erythrocytic stages of Plasmodium parasites, some of them at sub‐micromolar concentrations. The results of our research suggest that SAHAquines are promising leads for new anticancer and antimalarial agents.

show abstract

“…3) In recent years, the synthesis and biological evaluation of 1,2,4-triazole and 1,3,4-thiadiazole derivatives have become hot spots. Numerous of them possess antifungal, 4) antiglaucoma, 5) anti-inflammatory, 6) antioxidant, 7) and anticancer [8][9][10][11][12] activities and are of particular interest for medicinal chemists. In view of these observations, we designed and synthesized a series of new 1,2,4-triazole and 1,3,4-thiadiazole analogs and the structures of them were confirmed by 1 H-NMR, MS and elemental analysis.…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Potential Cytotoxic Agents

Shi

Song

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

A series of new 3-amino-5-sulfanyl-1,2,4-triazole and 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives have been synthesized and their cytotoxicities were evaluated on a panel of human cancer cell lines (BxPC-3, H1975, SKOV-3, A875, HCT116, etc.). The best one (compound 5m) exhibited activities with IC50 values ranging from 0.04 to 23.6 µM against nine human cancer cell lines. Further biological evaluation indicated that DNA replication was blocked by treatment with compound 5m in HCT116 cells.

show abstract

Synthesis, evaluation of anticancer activity and COMPARE analysis of N-bis(trifluoromethyl)alkyl-N’-substituted ureas with pharmacophoric moieties

Cited by 30 publications

References 57 publications

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

Synthesis and Biological Evaluation of 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Potential Cytotoxic Agents

Contact Info

Product

Resources

About