Design, synthesis and antitubercular assessment of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives.

A library of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives (7a-q) and (8a-j) were synthesized and evaluated for their in-vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The two compounds 7h and 8h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56 µg/mL respectively (MIC values of standard drugs; Ciprofloxacin 1.56 µg/mL & Ethambutol 3.12 µg/mL). Whereas, the four compounds 7i, 7n, 7p and 8i displayed noticeable antitubercular activity with a MIC value of 6.25 µg/mL. The active compounds of the series were further studied for their cytotoxicity against RAW264.7 cell line using MTT assay. Furthermore, to study the probable mechanism of antitubercular action, physicochemical property profiling, DFT calculation and molecular docking study were executed on mycobacterial cell wall target Decaprenylphosphoryl-ß-d-ribose 2'-epimerase 1 (DprE1). Among all the compounds, 7h (-10 kcal/mol) and 8h (-10.1 kcal/mol) exerted the highest negative binding affinity against the targeted DprE1 (PDB: 4NCR) protein.

Inhibition of protein tyrosine phosphatase 1B by serratane triterpenes from Huperzia serrata and their molecular docking study.

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from the natural resources, two new serratane triterpenes, 3-O-dihydro-p-coumaroyltohogenol (1) and 21-O-acetyltohogenol (2), along with four known serratane triterpenes (3-6), were isolated from the whole plant of Huperzia serrata. The chemical structures of compounds 1 and 2 were determined by NMR study, HRMS analysis, and chemical modification. All isolates were evaluated for their PTP1B inhibitory activities. Among the isolates, compounds 1, 3, 5 and 6 exhibit moderate inhibitory activities against PTP1B. Kinetic studies demonstrated that they are competitive inhibitors. Molecular docking studies support these experimental results by showing that compounds 1, 3, 5 and 6 interact with the active site of PTP1B, clarifying the structure-activity relationship. This study suggests that serratane triterpenes from H. serrata have potential as starting skeletons for anti-diabetes or anti-obesity agents.

Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments.

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

New polycyclic polyprenylated acylphloroglucinols with antidepressant activities from Hypericum perforatum L.

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1-6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo2(OCOCH3)4] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1-6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 µM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST) of mice, which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerted an antidepressant effect through the hypothalamic-pituitary-adrenal (HPA) axis.

Novel benzenesulfonamides as dual VEGFR2/FGFR1 inhibitors targeting breast cancer: Design, synthesis, anticancer activity and in silico studies.

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-ß kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.

Synthesis and biological evaluation of 2'-hydroxychalcone derivatives as AMPK activators.

A series of 2'-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration-response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 µM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKß, particularly compounds 27 (-8.4 kcal/mol) and 29 (-8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.

Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies.

A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS cancer (SNB-75), and ovarian cancer (OVAR-4) with IC50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and BAX proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Review of the recent advances of pyrazole derivatives as selective COX-2 inhibitors for treating inflammation.

Pyrazole heterocycle is regarded as an extremely significant agent for the therapy of inflammation. Celecoxib, lonazolac, deracoxib, and phenylbutazone are examples of commercially approved pyrazole drugs with COX-2 inhibitory potential for curing inflammation. There have been recently many reviews for the biological significance of pyrazole derivatives. This review talks about pyrazole derivatives with anti-inflammatory activity and also sheds the light on the recent updates on pyrazole research with an emphasis on some synthetic pathways utilized to construct this privileged scaffold and structure activity relationship that accounts for the anti-inflammatory activity in an attempt to pave the opportunity for medicinal chemists to develop novel anti-inflammatory agents with better COX-2 selectivity.

In Vitro and in Silico Study of New Biscoumarin Glycosides from Paramignya trimera against Angiotensin-Converting Enzyme 2 (ACE-2) for Preventing SARS-CoV-2 Infection.

In Vietnam, the stems and roots of the Rutaceous plant Paramignya trimera (Oliv.) Burkill (known locally as "Xáo tam phân") are widely used to treat liver diseases such as viral hepatitis and acute and chronic cirrhosis. In an effort to search for Vietnamese natural compounds capable of inhibiting coronavirus based on molecular docking screening, two new dimeric coumarin glycosides, namely cis-paratrimerin B (1) and cis-paratrimerin A (2), and two previously identified coumarins, the trans-isomers paratrimerin B (3) and paratrimerin A (4), were isolated from the roots of P. trimera and tested for their anti-angiotensin-converting enzyme 2 (ACE-2) inhibitory properties in vitro. It was discovered that ACE-2 enzyme was inhibited by cis-paratrimerin B (1), cis-paratrimerin A (2), and trans-paratrimerin B (3), with IC50 values of 28.9, 68, and 77 µM, respectively. Docking simulations revealed that four biscoumarin glycosides had good binding energies (∆G values ranging from -10.6 to -14.7 kcal/mol) and mostly bound to the S1' subsite of the ACE-2 protein. The key interactions of these natural ligands include metal chelation with zinc ions and multiple H-bonds with Ser128, Glu145, His345, Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots occur naturally in both cis- and trans-diastereomeric forms. The biscoumarin glycosides Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots hold potential for further studies as natural ACE-2 inhibitors for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Design, Green Synthesis and in silico Studies of New Substituted Naphtho[1,2-e][1,3]Oxazines as Potential Acetylcholinesterase Inhibitors.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors as the primary pharmacotherapy for numerous neurodegenerative conditions, leveraging their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, oxazines  have brought worthy synthetic interest due to their extensive biological activities including, anti-tubercular, anti-convulsant, and anti-cancer activities. In this study, a series of novel naphtho[1,2-e][1,3]oxazine derivatives has been designed  and synthesized with potential of acetylcholinesterase (AChE) inhibition. The target products have been prepared by a one-pot and three-component condensation reaction of 2-naphthol, aromatic aldehydes, and arylmethanimine in the presence of 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl) as an effective and recyclable catalyst under microwave irradiation solvent-free condition. The molecular docking studies has also been performed to investigate the synthetic compounds in the the AChE active site gorge. The results showed that all these derivatives interact with the enzymes with high affinity in binding pocket. The MM-GBSA studies were performed for all synthesized derivatives and among them, compound 3-(4-Chlorophenyl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine 5f, showed the lowest the binding free energy (-48.04 kcal mol-1). In general, oxazine derivatives could be proposed as the strong AChE inhibitors.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 µM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 µM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.

Construction and Docking Studies of Novel Pyrimido[4,5-b]quinolines as Antimicrobial Agents.

In order to develop novel antimicrobial agents, we prepared quinoline bearing pyrimidine analogues 2-7, 8 a-d and 9 a-d and their structures were elucidated by spectroscopic techniques. Furthermore, our second aim was to predict the interactions between the active compounds and enzymes (DNA gyrase and DHFR). In this work, fourteen pyrimido[4,5-b]quinoline derivatives were prepared and assessed for their antimicrobial potential by estimating zone of inhibition. All the screened candidates displayed antibacterial potential with zone of inhibition range of 9-24 mm compared with ampicillin (20-25 mm) as a reference drug. Moreover, the target derivatives 2 (ZI=16), 9 c (ZI=17 mm) and 9 d (ZI=16 mm) recorded higher antifungal activity against C. albicans to that exhibited by the antifungal drug amphotericin B (ZI=15 mm). Finally, the most potent pyrimidoquinoline compounds (2, 3, 8 c, 8 d, 9 c and 9 d) were docked inside DHFR and DNA gyrase active sites and they recorded excellent fitting within the active regions of DNA gyrase and DHFR. These outcomes revealed us that compounds (2, 3, 8 c, 8 d, 9 c and 9 d) could be lead compounds to discover novel antibacterial candidates.

Anticancer perspectives of monocarbonyl analogs of curcumin: A decade (2014-2024) review.

Monocarbonyl analogs of curcumin (MACs) represent structurally modified versions of curcumin. The existing literature indicates that MACs exhibit enhanced anticancer properties compared with curcumin. Numerous research articles in recent years have emphasized the significance of MACs as effective anticancer agents. This review focuses on the latest advances in the anticancer potential of MACs, from 2014 to 2024, including discussions on their mechanism of action, structure-activity relationship (SAR), and in silico molecular docking studies.

Novel C3-Methylene-Bridged Indole Derivatives with and without Substituents at N1: The Influence of Substituents on Their Hemolytic, Cytoprotective, and Antimicrobial Activity.

Alkaloids are natural compounds useful as scaffolds for discovering new bioactive molecules. This study utilized alkaloid gramine to synthesize two groups of C3-substituted indole derivatives, which were either functionalized at N1 or not. The compounds were characterized by spectroscopic methods. The protective effects of the new compounds against in vitro oxidative hemolysis induced by standard oxidant 2,2'-azobis(2-amidinopropane dihydro chloride (AAPH) on human erythrocytes as a cell model were investigated. Additionally, the compounds were screened for antimicrobial activity. The results indicated that most of the indole derivatives devoid of the N1 substitution exhibited strong cytoprotective properties. The docking studies supported the affinities of selected indole-based ligands as potential antioxidants. Furthermore, the derivatives obtained exhibited potent fungicidal properties. The structures of the eight derivatives possessing indole moiety bridged to the imidazole-, benzimidazole-, thiazole-, benzothiazole-, and 5-methylbenzothiazoline-2-thiones were determined by X-ray diffraction. The C=S bond lengths in the thioamide fragment pointed to the involvement of zwitterionic structures of varying contribution. The predominance of zwitterionic mesomers may explain the lack of cytoprotective properties, while steric effects, which limit multiple the hydrogen-bond acceptor properties of a thione sulfur, seem to be responsible for the high hemolytic activity.

Evaluation of Some Benzo[g]Quinazoline Derivatives as Antiviral Agents against Human Rotavirus Wa Strain: Biological Screening and Docking Study.

Globally, rotavirus (RV) is the most common cause of acute gastroenteritis in infants and toddlers; however, there are currently no agents available that are tailored to treat rotavirus infection in particular. Improved and widespread immunization programs are being implemented worldwide to reduce rotavirus morbidity and mortality. Despite certain immunizations, there are no licensed antivirals that can attack rotavirus in hosts. Benzoquinazolines, chemical components synthesized in our laboratory, were developed as antiviral agents, and showed good activity against herpes simplex, coxsackievirus B4 and hepatitis A and C. In this research project, an in vitro investigation of the effectiveness of benzoquinazoline derivatives 1-16 against human rotavirus Wa strains was carried out. All compounds exhibited antiviral activity, however compounds 1-3, 9 and 16 showed the greatest activity (reduction percentages ranged from 50 to 66%). In-silico molecular docking of highly active compounds, which were selected after studying the biological activity of all investigated of benzo[g]quinazolines compounds, was implemented into the protein's putative binding site to establish an optimal orientation for binding. As a result, compounds 1, 3, 9, and 16 are promising anti-rotavirus Wa strains that lead with Outer Capsid protein VP4 inhibition.

Biological Investigation of 2-Thioxo-benzo[g]quinazolines against Adenovirus Type 7 and Bacteriophage Phi X174: An In Vitro Study.

Mortality and morbidity caused by viruses are a global health problems. Therefore, there is always a need to create novel therapeutic agents and refine existing ones to maximize their efficacy. Our lab has produced benzoquinazolines derivatives that have proven effective activity as antiviral compounds against herpes simplex (HSV 1 and 2), coxsackievirus B4 (CVB4), and hepatitis viruses (HAV and HCV). This in vitro study was aimed at investigating the effectiveness of benzoquinazoline derivatives 1-16 against adenovirus type 7 and bacteriophage phiX174 using a plaque assay. The cytotoxicity against adenovirus type 7 was also performed in vitro, using a MTT assay. Most of the compounds exhibited antiviral activity against bacteriophage phiX174. However, compounds 1, 3, 9, and 11 showed statistically significant reductions of 60-70% against bacteriophage phiX174. By contrast, compounds 3, 5, 7, 12, 13, and 15 were ineffective against adenovirus type 7, and compounds 6 and 16 had remarkable efficacy (50%). Using the MOE-Site Finder Module, a docking study was carried out in order to create a prediction regarding the orientation of the lead compounds (1, 9, and 11). This was performed in order to investigate the activity of the lead compounds 1, 9, and 11 against the bacteriophage phiX174 by locating the ligand-target protein binding interaction active sites.

Association of antiviral drugs and their possible mechanisms with DRESS syndrome using data mining algorithms.

Antiviral drugs are not known for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The current study aims is to find out the association of antiviral drugs and their possible mechanism with DRESS. Data mining algorithms such as proportional reporting ratio that is, PRR (≥2) with associated χ2  value (>4), reporting odds ratio that is, ROR (≥2) with 95% confidence interval and case count (≥3) were calculated to identify a possible signal. Further, molecular docking studies were conducted to check the interaction of selected antiviral drugs with possible targets. The potential signal of DRESS was found to be associated with abacavir, acyclovir, ganciclovir, lamivudine, lopinavir, nevirapine, ribavirin, ritonavir, and zidovudine among all selected antiviral drugs. Further, subgroup analysis has also shown a potential signal in different age groups and gender. The sensitivity analysis results have shown a decrease in the strength of the signal, however, there was no significant impact on the outcome except for acyclovir. The docking results have indicated the possible involvement of human leukocyte antigen (HLA)*B1502 and HLA*B5801. The positive signal of DRESS was found with selected antiviral drugs except for acyclovir.

2-[(2-Amino-6-methylpyrimidin-4-yl)sulfanyl]-N-arylacetamides: Discovery of a new class of anti-tubercular agents and prospects for their further structural modification.

The synthesis of 2-[(2-amino-6-methylpyrimidin-4-yl)sulfanyl]-N-arylacetamides 6a-j was encouraged by their antibacterial activity and drug-likeness predictions. Of the compounds, two bearing 4­isopropylphenyl 6c and 2,5­dichlorophenyl 6i moieties were found to be threefold more potent than the first-line tuberculosis drug ethambutol. A molecular docking study revealed that compound 6c may selectively bind to cyclopropane mycolic acid synthase 1, an enzyme essential for the construction of the tuberculosis bacteria cell wall. Keeping this in mind, a recently developed ligand-based virtual screening strategy combining the molecular similarity search and docking approaches was adopted to identify more potent analogs of the parent compound. As a result, a series of new ligands 18p-w with phenyl-substituted azinyl amide groups were in silico discovered. Due to their high binding affinities to the enzyme and improved toxicity profiles, the ligands are undoubtedly worth future synthetic efforts.

CRBN ligand expansion for hematopoietic prostaglandin D2 synthase (H-PGDS) targeting PROTAC design and their in vitro ADME profiles.

An increasing number of research reports are describing modifications of the E3 ligand, in particular, cereblon (CRBN) ligands, to improve the chemical and metabolic stabilities as well as the physical properties of PROTACs. In this study, phenyl-glutarimide (PG) and 6-fluoropomalidomide (6-F-POM), recently used as CRBN ligands for PROTAC design, were applied to hematopoietic prostaglandin D2 synthase (H-PGDS)-targeted PROTACs. Both PROTAC-5 containing PG and PROTAC-6 containing 6-F-POM were found to have potent activities to induce H-PGDS degradation. Furthermore, we obtained in vitro ADME data on the newly designed PROTACS as well as our previously reported PROTACs(H-PGDS) series. Although all PROTACs(H-PGDS) are relatively stable toward metabolism, they had poor PAMPA values. Nevertheless, PROTAC-5 showed Papp values similar to TAS-205, which is in Phase 3 clinical trials, and is expected to be the key to improving the pharmacokinetics of PROTACs.

Promising Cytotoxic butenolides from the Soybean endophytic fungus Aspergillus terreus: a combined molecular docking and in-vitro studies.

AIM: This study aimed to use one strain many compounds approach (OSMAC) to investigate the cytotoxic potential of Aspergillus terreus associated with soybean versus several cancer cell lines, by means of in-silico and in vitro approaches. METHODS AND RESULTS: Fermentation of the isolated strain was done on five media. The derived extracts were investigated for their inhibitory activities against three human cancer cell lines; mammary gland breast cancer (MCF-7), colorectal adenocarcinoma (Caco-2), and hepatocellular carcinoma (HepG2) using MTT Assay. The fungal mycelia fermented in Modified Potato Dextrose Broth (MPDB) was the most cytotoxic extract against HepG2, MCF-7, and Caco-2 cell lines with IC50 4.2 ± 0.13, 5.9 ± 0.013 and 7.3 ± 0.004 µg mL-1, respectively. MPDB extract was scaled up resulting in the isolation of six metabolites; three fatty acids (1, 2, and 4), one sterol (3) and two butenolides (5 and 6) by column chromatography. The isolated compounds (1-6) were screened through a molecular docking approach for their binding aptitude to various active sites. butyrolactone-I (5) revealed a significant interaction within the CDK2 active site, while aspulvinone E (6) showed promising binding affinity to FLT3 and EGFR active sites that was confirmed by in vitro CDK2, FLT3 and EGFR inhibitory activity. Finally, the in vitro cytotoxic activities of butyrolactone-I (5) and aspulvinone E (6) revealed the antiproliferative activity of butyrolactone-I (5), against HepG2 cell line (IC50 = 17.85 ± 0.32 µM). CONCLUSION: Molecular docking analysis and in vitro assays suggested the CDK2/A2 inhibitory potential of butyrolactone-I (5) in addition to the promising interaction abilities of aspulvinone E (6) with EGFR and FLT3 active sites as a possible mechanism of their biological activities.