Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors.

ABSTRACT: Thymidylate synthase (TS) has been an attention-grabbing area of research for the treatment of cancers due to their role in DNA biosynthesis. In the present study, we have synthesised a library of thiazolidinedione-1,3,4-oxadiazole hybrids as TS inhibitors. All the synthesised hybrids followed Lipinski and Veber rules which indicated good drug likeness properties upon oral administration. Among the synthesised hybrids, compound 9 and 10 displayed 4.5 and 4.4 folds activity of 5-Fluorouracil, respectively against MCF-7 cell line whereas 3.1 and 2.5 folds cytotoxicity against HCT-116 cell line. Furthermore, compound 9 and 10 also inhibited TS enzyme with IC₅₀ = 1.67 and 2.21 µM, respectively. Finally, the docking studies of 9 and 10 were found to be consistent with in vitro TS results. From these studies, compound 9 and 10 has the potential to be developed as TS inhibitors.

SUBMITTER: Alzhrani ZMM

PROVIDER: S-EPMC7241536 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

Project description:In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.

| S-EPMC8725909 | biostudies-literature

Novel hybrids of thiazolidinedione-1,3,4-oxadiazole derivatives: synthesis, molecular docking, MD simulations, ADMET study, in vitro, and in vivo anti-diabetic assessment.

Project description:As compared to standard medicinal compounds, hybrid molecules that contain multiple biologically active functional groups have greater affinity and efficiency. Hence based on this concept, we predicted that a combination of thiazolidinediones and 1,3,4-oxadiazoles may enhance α-amylase and α-glucosidase inhibition activity. A series of novel 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)thiazolidine-2,5-dione derivatives (5a-5j) were synthesized and characterized using different spectroscopic techniques i.e., FTIR, 1H-NMR, 13C-NMR and MS. To evaluate in silico, molecular docking, MMGBSA, and MD simulations were carried out which were further evaluated via in vitro inhibition of α-amylase and α-glycosidase enzyme inhibition assays. In addition, the in vivo study was performed on a genetic model of Drosophila melanogaster to assess the antihyperglycemic effects. The compounds (5a-5j) demonstrated α-amylase and α-glucosidase inhibitory activity in the range of IC50 values 18.42 ± 0.21-55.43 ± 0.66 μM and 17.21 ± 0.22-51.28 ± 0.88 μM respectively when compared to standard acarbose. Based on the in vitro studies, compounds 5a, 5b, and 5j were found to be potent against both enzymes. In vivo studies have shown that compounds 5a, 5b, and 5j lower glucose levels in Drosophila. These compounds could be further developed in the future to produce a new class of antidiabetic agents.

| S-EPMC9828437 | biostudies-literature

Naproxen Based 1,3,4-Oxadiazole Derivatives as EGFR Inhibitors: Design, Synthesis, Anticancer, and Computational Studies.

Project description:A library of novel naproxen based 1,3,4-oxadiazole derivatives (8-16 and 19-26) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hybrids, compound2-(4-((5-((S)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol(15) was the most potent compound against MCF-7 and HepG2cancer cells with IC50 of 2.13 and 1.63 µg/mL, respectively, and was equipotent to doxorubicin (IC50 1.62 µg/mL) towards HepG2. Furthermore, compound 15 inhibited EGFR kinase with IC50 0.41 μM compared to standard drug Erlotinib (IC50 0.30 μM). The active compound induces a high percentage of necrosis towards MCF-7, HePG2 and HCT 116 cells. The docking studies, DFT and MEP also supported the biological data. These results demonstrated that these synthesized naproxen hybrids have EGFR inhibition effects and can be used as leads for cancer therapy.

| S-EPMC8469912 | biostudies-literature

Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.

Project description:Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-l-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity.

| S-EPMC6829050 | biostudies-literature

Apoptosis Inducing 1,3,4-Oxadiazole Conjugates of Capsaicin: Their In Vitro Antiproliferative and In Silico Studies.

Project description:A series of 1,3,4-oxadiazole tethered capsaicin derivatives was prepared by using one point modification at the vanillyl-hydroxyl group of capsaicin. All the prepared capsaicinoids were evaluated for their antiproliferative activity against NCI-60 human cancer cell lines at 10 μM. Among the compounds tested, compound 20a exhibited good cytotoxic activity against HCT-116, NCI-H460, and SKOV3 cell lines with IC50 8.55 μΜ, 5.41 μΜ, and 6.4 μΜ, respectively, compared to the parent natural product capsaicin. Further on, it significantly inhibited the colony formation in NCI-H460 in a dose dependent manner and enhanced the ROS effect. It also caused cell arrest at the S phase and induced apoptosis via suppressing the Pro parp marker. Compound 20a exhibited an antimigratory property and suppressed the expression of the VEGF marker in a dose dependent manner. Furthermore, compound 20a also suppressed the effects of the p-Erk, p-p38, and P-CNA makers. In silico studies supported the interaction of this class of compounds with the VEGFR2 protein.

| S-EPMC8591727 | biostudies-literature

1,3,4-oxadiazole/chalcone hybrids: Design, synthesis, and inhibition of leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities.

Project description:A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC50 of 1.95?µM, 2.36?µM and 3.45?µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC50?=?0.24??M), Src (IC50?=?0.96??M), and IL-6 (% of control?=?20%). Additionally, most of the compounds decreased STAT3 activation.

| S-EPMC6923798 | biostudies-literature

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment.

Project description:A new chemical library based on the hybridization of cholic acid with the heterocyclic moiety 1,3,4-oxadizole was synthesized, and tested for antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. Among the synthesized compounds, the most potent derivatives against S. aureus were 4t, 4i, 4p, and 4c with MIC values between 31 and 70 µg/mL, while compound 4p was the most active one against Bacillus subtilis with a MIC value of 70 µg/mL. Interestingly, compounds 4a and 4u exerted selective activity against Gram-positive bacteria. The synthesized compounds showed good activity against A. fumigatus and C. albicans and compound 4v exhibited selective activity against fungi only.

| S-EPMC9174839 | biostudies-literature

N-Acylbenzenesulfonamide Dihydro-1,3,4-oxadiazole Hybrids: Seeking Selectivity toward Carbonic Anhydrase Isoforms.

Project description:A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racemic mixture led to the isolation of the levorotatory eutomer exhibiting an increase of hCA XII inhibition potency and selectivity with respect to hCA II. Computational studies corroborated these data. Overall our data indicate that both substitution pattern and stereochemistry of dihydro-1,3,4-oxadiazole could be considered as key factors to determine activity and selectivity toward hCA isozymes. These results can provide further indication for the design and optimization of selective hCA inhibitors.

| S-EPMC5554910 | biostudies-literature

Design, synthesis, and pharmacology of some oxadiazole and hydroxypyrazoline hybrids bearing thiazoyl scaffold: antiproliferative activity, molecular docking and DNA binding studies.

Project description:A series of oxadiazole (7a-l) and hydroxypyrazoline derivatives (8a-l) incorporating thiazole were synthesized and characterized by spectral analysis (1H-NMR, 13C-NMR, Mass, and FT-IR). The synthesized compounds were screened for their in vitro cytotoxicity against MDA-MB231 and HT-29 human cell lines. Conjugates 7d, 7e, 7f, 7i, 7l, 8a, 8b, 8i and 8l exhibited significant antiproliferative activity on both MDA-MB231 and HT-29 cell lines. Flow cytometric analysis reveals that, 7i arrests both cells lines at Go/G1 phase whereas 8i induced G0/G1 arrest only in the HT-29 cells. Furthermore, Computational interaction studies of 7i and 8i exhibited its capacity of being a plausible CDK2 and BCL-2 inhibitor respectively. In addition, DNA binding of the synthesized compounds and DNA docking of 7i and 8i demonstrated the ability to interact with DNA. Compounds 7i and 8i causes' remarkable growth inhibition of MDA-MB231 and HT-29 cells but compound 8i was considerably effective against HT-29 cells. Overall these compounds can be practiced for further drug development.

| S-EPMC6393698 | biostudies-literature

New 1,2,3-Triazole/1,2,4-triazole Hybrids as Aromatase Inhibitors: Design, Synthesis, and Apoptotic Antiproliferative Activity.

Project description:A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a-i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a-i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores.

| S-EPMC10609154 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data