A group of EGFR inhibitors derived from thieno2,3-dpyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the ...most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFR
WT
and EGFR
T790M
, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFR
WT
and EGFR
T790M
indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.
Continuing our antecedent work against COVID-19, a set of 5956 compounds of traditional Chinese medicine have been virtually screened for their potential against SARS-CoV-2 helicase (PDB ID: 5RMM). ...Initially, a fingerprint study with VXG, the ligand of the target enzyme, disclosed the similarity of 187 compounds. Then, a molecular similarity study declared the most similar 40 compounds. Subsequently, molecular docking studies were carried out to examine the binding modes and energies. Then, the most appropriate 26 compounds were subjected to in silico ADMET and toxicity studies to select the most convenient inhibitors to be: (1R,2S)-ephedrine (57), (1R,2S)-norephedrine (59), 2-(4-(pyrrolidin-1-yl)phenyl)acetic acid (84), 1-phenylpropane-1,2-dione (195), 2-methoxycinnamic acid (246), 2-methoxybenzoic acid (364), (R)-2-((R)-5-oxopyrrolidin-3-yl)-2-phenylacetic acid (405), (Z)-6-(3-hydroxy-4-methoxystyryl)-4-methoxy-2H-pyran-2-one (533), 8-chloro-2-(2-phenylethyl)-5,6,7-trihydroxy-5,6,7,8-tetrahydrochromone (637), 3-((1R,2S)-2-(dimethylamino)-1-hydroxypropyl)phenol (818), (R)-2-ethyl-4-(1-hydroxy-2-(methylamino)ethyl)phenol (5159), and (R)-2-((1S,2S,5S)-2-benzyl-5-hydroxy-4-methylcyclohex-3-en-1-yl)propane-1,2-diol (5168). Among the selected 12 compounds, the metabolites, compound 533 showed the best docking scores. Interestingly, the MD simulation studies for compound 533, the one with the highest docking score, over 100 ns showed its correct binding to SARS-CoV-2 helicase with low energy and optimum dynamics. Finally, MM-PBSA studies showed that 533 bonded favorably to SARS-CoV-2 helicase with a free energy value of −83 kJ/mol. Further, the free energy decomposition study determined the essential amino acid residues that contributed favorably to the binding process. The obtained results give a huge hope to find a cure for COVID-19 through further in vitro and in vivo studies for the selected compounds.
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•New azetidine-thiourea hybrids were designed and synthesized as VEGFR-2 inhibitors.•3B was found to be more potent than Doxorubicin in PC3, A431 and 786-O cell lines.•ADMET, VEGFR-2 ...moleuclar docking and DFT studies were carried out.•Compounds possess druglikeness characteristics as it showed low toxicity and good absorption.
With the aim to discover potent and novel antitumor agents, a series of thiourea compounds bearing 3-(4-methoxyphenyl)azetidine moiety were designed according to the essential pharmacophoric features of the reported VEGFR-2 inhibitors and synthesized. All the synthesized compounds were evaluated for their in vitro anticancer activity against various human cancer cell lines (lung (A549), prostate (PC3), breast (MCF-7), liver (HepG2), colon (HCT-116), ovarian (SKOV-3), skin (A431), brain (U251) and kidney (786-O)). 3-(4-Methoxy-3-(2-methoxypyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (3B) was found to be most potent member against PC3, U251, A431, and 786-O cancer cell lines with EC50 values 0.25, 0.6, 0.03, and 0.03 µM, respectively and showed more potency than Doxorubicin in PC3, A431, and 786-O cell lines. Compounds 1B to 7B showed EC50 values ranging from 0.03 to 12.55 µM in A431 cell line. Compound 3-(4-methoxy-3-(pyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (1B) was found to be highly efficient in A431 and 786-O cell line with EC50 values of 0.77 and 0.73 µM respectively. All the compounds exhibited good to moderate cytotoxic activity. The pharmacophoric features and molecular docking studies confirmed the potentialities of compounds 1B, 2B, 3B and 5B to be VEGFR-2 inhibitors. Moreover, in silico ADMET prediction indicated that most of the synthesized compounds have drug-like properties, possess low adverse effects and toxicity. In addition, the DFT studies for the most active compounds (1B and 3B) were carried out. In the end, our studies revealed that the compounds 1B and 3B represent promising anticancer potentialities through their VEGFR-2 inhibition.
This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested
to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these ...compounds, 15a showed the highest cytotoxicity against HepG2, with an IC
value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC
value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64, respectively. Moreover, 15a demonstrated potent VEGFR-2 inhibitory activity (IC
= 0.239 μM). Further investigations revealed that 15a induced apoptosis in HepG2 cells, significantly increasing early-stage and late-stage apoptosis percentages from 3.06% and 0.71% to 29.49% and 9.63%, respectively. It also upregulated caspase-3 and caspase-9 levels by 3.45-fold and 2.37-fold, respectively compared to control HepG2 cells. Additionally, 15a inhibited the migration and wound healing ability of HepG2 cells. Molecular docking confirmed the binding affinities of the semi-synthesized compounds to VEGFR-2, consistent with
results. Several computational analyses (DFT, MD simulations, MM-GBSA, PLIP, and essential dynamics) supported the stability of the 15a-VEGFR-2 complex. Overall, the biological and computational findings suggest that compound 15a could be a promising lead compound for the development of a novel apoptotic anticancer agent.
L. is a widely cultivated herbal medicinal plant in China and other countries. In this study, two new 2, 3-dihydrobenzofuran glucosides (
,
) and fourteen known metabolites (
-
) were isolated from ...the stems and leaves of
(SLT). The chemical structures of the isolated compounds were characterized comprehensively based on one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Absolute configurations of compounds
and
were determined by ECD calculations. Compounds
and
exhibited moderate in vitro inhibitory activities against human gastric cancer cell lines (AGS) with IC
values of 41.20 μmol/L and 30.43 μmol/L, respectively. The fingerprint profiles of stems and leaves of
with three color types of flowers (Janie Yellow Bright, Jinmen Orange, Shouyao Red and Yellow color) were established by high-performance liquid chromatography (HPLC). Ten different batches of stems and leaves were examined as follow: Shouyao Red and Yellow color (1, 2, 3), Janie Yellow Bright (4, 5, 6, 7) and Jinmen Orange (8, 9, 10). Twenty-two common peaks were identified with similarity values ranging from 0.910 to 0.977. Meanwhile, the average peak area of SLT in the three types of flowers was different and it was the highest in Janie Yellow Bright.
This study aims to design and evaluate (
and
) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following
studies were performed; DFT ...calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's
(ADMET) analysis was also conducted. Subsequently, the compound ((E)-
-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound
.
, VEGFR-2 inhibition and cytotoxicity of compound
against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound
were also evaluated.
DFT calculations assigned stability and reactivity of compound
. Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound
's correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The
assays demonstrated that compound
effectively inhibited VEGFR-2, with an IC
value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC
values of 57.93 and 78.82 μM, respectively. Importantly, compound
exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC
= 164.12 μM). Additionally, compound
significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal.
In summary, the presented study has identified compound
as a promising candidate for the development of a novel apoptotic lead anticancer drug.
A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1
H
-purin-1-yl)-
N
-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural ...characteristics to interact with EGFR’s pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (
T-1-DOMPA
). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of
T-1-DOMPA
. Then,
T-1-DOMPA
’s anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies,
T-1-DOMPA
bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of
T-1-DOMPA
were computed before preparation, and its drug-likeness was anticipated. Therefore,
T-1-DOMPA
was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of
T-1-DOMPA
against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC
50
value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly,
T-1-DOMPA
inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC
50
values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally,
T-1-DOMPA
prevented effectively the MDA-MB-231cell line’s healing and migration abilities. Also,
T-1-DOMPA
’s abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally,
T-1-DOMPA
caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell.
Objective. This study aimed to investigate the preparation of patuletin-encapsulated chitosan nanoparticles (PT-CS-NPs) using the ionic gelation method, evaluate their potential as anticancer agents, ...and invent a new method of differential pulse voltammetric analysis for patuletin (PT). Methods. Computational studies were conducted to assess the affinity of PT for chitosan, confirming a promising interaction. PT-CS-NPs were synthesized based on the computational outputs, resulting in nanoparticles with an angular structure and an average size of 6.168 nm. The cytotoxicity of PT and PT-CS-NP was evaluated in breast and colon cancer cell lines, and selectivity indices were calculated to assess safety profiles. The electrochemical behavior of PT was also investigated using the Britton–Robinson buffer. Results. PT-CS-NP exhibited both potent cytotoxicity and a favorable safety profile, showing the most active and safest pattern of cytotoxicity among the tested compounds. The electrochemical oxidation of PT was observed at 0.531 V vs. Ag/AgCl at pH 4.0.0. The concentration of PT showed a linear relationship with the corresponding peak current over the range of 10.0 x 10−9:10.0 x 10−5MM, with a minimum limit of detection of 3.4 × 10(−9)M. The proposed method successfully measured PT, with a relative standard deviation below 2%. Conclusion. The preparation of PT-CS-NP via the ionic gelation method resulted in angular nanoparticles with a promising anticancer activity and safety profiles. The electrochemical behavior of PT was characterized, and a reliable method for PT quantification was established.
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•Eighteen compounds of novel quinoxaline derivatives were designed and synthesized.•Molecular docking and pharmacophore studies were carried out.•In vivo anti-hyperglycemic activity, ...in vitro PPARγ binding affinity and insulin-secreting ability were carried out.•Some of the synthesized compounds showed promising anti-hyperglycemic activity.
In our effort to develop potent anti-hyperglycemic agents with potential agonistic activities toward PPARγ and SUR, three novel series of quinoxaline derivatives bearing sulfonylurea or sulfonylthiourea moieties with different linkers were designed and synthesized. Some of the newly synthesized compounds were evaluated in vivo for their anti-hyperglycemic activities in STZ-induced hyperglycemic rats. Compounds 15a, 15e, 19b and 24a exhibited the highest anti-hyperglycemic activities with % reduction in blood glucose level of (50.58, 43.84, 45.10 and 49.62, respectively). Additionally, eight compounds revealed potent anti-hyperglycemic activities were further evaluated in vitro for their PPARγ binding affinity and insulin-secreting ability as potential mechanisms for anti-hyperglycemic activity. Four compounds (15a, 15b, 15d and 15e) significantly bound to PPARγ with IC50 values of 0.482, 0.491, 0.350 and 0.369μM, respectively. Moreover, Compounds 15a and 15b have demonstrated induction of insulin-secretion with EC50 values of 0.92 and 0.98μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively.
Background: Human African trypanosomiasis is one of the most serious neglected tropical diseases causing fatal symptoms and death. Natural products are a main source for anti-infective metabolites. ...Objectives: The objective of the study is to evaluate eight different plants belonging to the Kalanchoe species growing in Egypt for antitrypanosomal, antimalarial, antileishmanial, cytotoxic, and antimicrobial activities. Materials and Methods: The antitrypanosomal activity against Trypanosoma brucei; cytotoxic activities against human colon carcinoma, human hepatocyte carcinoma, and human breast adenocarcinoma cell lines; antileishmanial activity against Leishmania donovani; antimalarial activity against Plasmodium falciparum; and antimicrobial activities of all plant extracts have been examined. As well as the identification of the secondary metabolites for the most active extract was performed via ultra performance liquid chromatography coupled to high resolution quadrupole time of flight mass spectrometer operated in negative and positive ionization modes. Results: Among the examined plant extracts, Kalanchoe longiflora leaves extract showed promising activity against T. brucei with an inhibition concentration of sample at 50% fall in absorbance (IC50) value of 17.6 μg/mL. K. longiflora with other extracts exhibited promising cytotoxic activities. Profiling of the polar secondary metabolites of K. longiflora revealed the presence of 47 metabolites including 31 flavonoids, 9 phenolic acids, 4 anthocyanidins, 2 chalcone glucoside, and 1 coumarin. To determine the mechanism of action of K. longiflora extract as a potent antitrypanosomal and cytotoxic agent, we investigate its ability to inhibit topoisomerase I enzyme. K. longiflora extract showed an excellent activity with an IC50 value of 0.148 μg/mL. Conclusion: These interesting results open the door for further research aiming at the development of a successful treatment for Trypanosoma from K. longiflora.
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