SYNTHESIS, ANTICANCER EVALUATION AND MOLECULAR MODELING OF SOME SUBSTITUTED THIAZOLIDINONYL AND THIAZOLYL PYRAZOLE DERIVATIVES

Objective: The present work aimed to synthesize some new substituted thiazoles incorporated to pyrazole moiety starting from 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (1) in order to evaluate their anticancer activity and GSTP1 inhibition in a trail to explore new potential GST inhibitors and prevent the resistance of cells to anticancer drugs. In addition, investigate the probability of the most promising cytotoxic compounds to inhibit GSTP1 enzyme via molecular docking study.Methods: The carboxaldehyde 1 was treated with substituted thiosemicarbazide in absolute ethanol to give the corresponding thiosemicarbazone derivatives 2a–d. Cyclization of 2a-d either by ethyl bromoacetate, phenacyl bromide or maleic acid anhydride furnished new thiazole derivatives 3, 4 and 5, respectively. These target compound 2-5 were screened for their GSTP1 inhibition and cytotoxic activity against HEPG-2 (human liver carcinoma), A549 (human lung carcinoma) and PC3 (human prostate carcinoma). Finally, molecular docking study of the most promising cytotoxic compounds against GSTP1 (PDB ID: 3GUS) is discussed.Results: Compounds 4a, 4b, and 4d were found to be highly active against HEPG-2 and PC-3 cancer cell lines with IC50 values ranging from 0.2±0.81 to 9.3±2.08 μM compared to doxorubicin with IC50= 37.8±1.50 and 41.1±2.01 μM, respectively. Screening of 4a, 4b and 4d against GSTP1 showed higher inhibition activity with IC50 ranging from 1.5±0.18 to 4.3±0.29 μM. Docking studies revealed the promising binding affinities of the latter compounds which match with the binding mode of the ligand, NBDHEX toward the active site of GSTP1.Conclusion: Compounds 4a, 4b and 4d were distinguished by the higher anticancer activity against HEPG-2, A-549 and PC-3 cell lines of tumor and the remarkable inhibitory activity against GSTP1

Screening of natural products for therapeutic activity against solid tumors

258-264Most of the currently used cancer therapeutics are natural products. These agents were generally discovered based on their toxicity to tumour cells using various bioassays. Although the exact mechanisms of action of the most commonly used cancer therapeutics such as anthracyclins, podophyllotoxins and camptothecin are incompletely understood, it is becoming increasingly clear that these agents often show complex modes of action at the cellular level, interacting with numerous targets. Such complex modes of action may be the very reason for clinical efficacy. For discovering new cytotoxic anticancer drugs sophisticated screening methods were used. The principles of such screening projects conducted, using collections of purified natural products or extracts from plants have been described. By performing simple but robust pre-screening tests such as the brine shrimp assay, bioactive extracts can be identified. Extracts (65) prepared from a collection of Egyptian plants were identified that showed cytotoxity on HepG2 cells. Interestingly, 22 (33%) of these raw extracts, induced > 2-fold induction of caspase-cleavage activity in a colon carcinoma cell line, consistent with induction of apoptosis. Only a fraction of the diversity of the biosphere has been tested for biological activity and novel cancer therapeutics remains to be discovered

SYNTHESIS, MOLECULAR DOCKING AND ANTI-PROLIFERATIVE ACTIVITY OF NEW SERIES OF 1-METHYLSULPHONYL-3-INDOLYL HETEROCYCLES

Objective: The present work aimed to synthesize a new series of 1-methylsulphonyl-3-indolyl heterocycles and study their cytotoxic activity. In addition, we attempted to explore the mode of the interaction of anti-proliferative compounds with the active site of carbonic anhydrase IX (CA IX) theoretically via molecular docking study.Methods: Novel series of pyrazole, pyrimidine and triazole derivatives bearing 1-methylsulphonyl-1H-indole were prepared via a series of hetero cyclization reactions utilizing 3-(1-methylsulphonyl-1H-indol-3-yl)-1-(substituted phenyl)-1H-pyrazole-4-carboxaldehydes 3a-d and 3-chloro-3-(1-methylsulphonyl-1H-indol-3-yl)propenal (6) and evaluating their anti-proliferative activity. The structures of the newly synthesized compounds were confirmed by elemental analyses, IR, NMR and mass spectral data. In addition, molecular docking study of the most promising antiproliferative compounds against the active site of carbonic anhydrase IX (PDB ID: 4BCW) theoretically is discussed.Results: Compounds 5c, 7 and 12 revealed potent anti-proliferative effects against A-549 cancer cell line with IC50 of 44.3, 17.2 and 38.7 µmol/l, respectively compared to the reference drug doxorubicin (IC50 of 48.8 µmol/l). While compound 5c was found to be highly active with IC50 of 5.66 µmol/l against HCT-116 cancer cell line than doxorubicin (IC50 of 65.00 µmol/l).Conclusion: Further work is recommended to confirm the inhibition of CA IX in a specific bioassay

Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives

A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a–g and 11a–g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofurans (1b) and their α,β-unsaturated keto derivatives 6a–g and 7a–g with chlorosulfonyl isocyanate (CSI). On the other hand, N-chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a–g, and 11a–g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical-scavenging activity compared to ascorbic acid at 100 μg/mL. 4,9-Dimethoxy-5-substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 μmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 μmol/mL, respectively

Kinase Inhibitory Activities and Molecular Docking of a Novel Series of Anticancer Pyrazole Derivatives

A series of novel 1,3,4-triarylpyrazoles containing different heterocycles has been prepared, characterized and screened for their in vitro antiproliferative activity against HePG-2, MCF-7, PC-3, A-549 and HCT-116 cancer cell lines. The biological results revealed that compound 6 showed the highest anticancer activity so it was subjected to a kinase assay study where it reduced the activity of several protein kinases including AKT1, AKT2, BRAF V600E, EGFR, p38α and PDGFRβ at 100 μM using the radiometric or ADP-Glo assay method. Molecular docking simulation supported the initial kinase assay and suggested a common mode of interaction at the ATP-binding sites of these kinases, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further research

Ethnopharmacological Survey on Medicinal Plants Used by Traditional Healers in Central and Kara Regions of Togo for Antitumor and Chronic Wound Healing Effects

Cancer is an emerging public health problem in sub-Saharan Africa. Several medicinal plants are used by traditional healers to treat tumors. In Togo, there are no recorded data for these plants but traditional healers claim to cure tumors with some success. So, information on medicinal plants used to cure human tumors and cancer could be of great importance for their widespread use and scientific validation. The present ethnopharmacological survey aims to record information on antitumor plants in central and Kara regions of Togo. Semistructured validated questionnaires were administered to fifty-seven traditional healers specialized in tumor management in 7 prefectures of Togo. Good practices and know-how were recorded. Quantitative ethnobotanical tools were used to analyze and summarize the data collected. 85 recipes of medicinal plants for tumors management are provided. In the local dialect, 78.95% of traditional healers do not have a clear tumor designation and 29.90% find that the causes of tumors remain unknown. According to 48.78% of traditional healers, the diagnosis of tumors in patients is made in the hospital. The types of tumors frequently treated are those of the breast (43.75%) and the lung (16.67%). The seventy listed medicinal plants belong to thirty-nine families, the most represented being Rubiaceae (17.95%), Caesalpiniaceae (12.82%), Fabaceae (10.26%), and Annonaceae (7.69%). The ten most cited species were Xylopia aethiopica, Aframomum melegueta, Khaya senegalensis, Parkia biglobosa, Piliostigma thonningii, Blighia sapida, Vitellaria paradoxa, Adansonia digitata, Annona muricata, and Parinari curatellifolia. Most of the recipes are prepared as decoction (40%) and administered orally (54.12%). Both regions of our study have a wealth of medicinal plants, and traditional healers would use their local knowledge in the management of various tumors and chronic wounds

Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC 0.03 mM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors