Tackling microbial resistance with 4H-chromen-4-one derivatives as a novel class of penicillin binding protein 2a inhibitors.

With the continued upsurge of antibiotic resistance and reduced susceptibility to almost all frontline antibiotics, there is a pressing need for the development of new, effective, and safe alternatives. In this study, a scaffold-hopping strategy was utilized to develop a novel class of penicillin-binding protein 2a (PBP2a) inhibitors, centered around a 4H-chromen-4-one core structure. These newly designed compounds demonstrated strong antibacterial efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant gram-positive pathogens.

Structural Optimization and MD Simulation Study of Benzimidazole Derivatives as Potent Mutant FLT3 Kinase Inhibitors Targeting AML.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor survival rates in adults, posing a significant economic burden. FMS-like tyrosine kinase 3 (FLT3) mutations are linked to poor prognosis in AML and resistance to clinically approved FLT3 inhibitors. Previously, we reported a novel benzimidazole-based FLT3 inhibitor, 4ACP, with nanomolar activities against FLT3-ITD and FLT3-TKD mutants, showing selective cytotoxicity against FLT3-ITD AML cell lines.

A synthetic molecule targeting STAT3 against human oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC), one of the most common cancers in Taiwan, needs new therapeutic agents and treatments. The aim of this study was to investigate the anti-proliferative activity of {-[3-chloro-4-[5-[3-[[[4-[(cyclopropylcarbonyl)-amino]3-(trifluoromethyl)phenylamino]carbonyl]amino]phenyl]-1,2,4-oxadiazol-3-yl]phenyl]-3-pyridine-carboxamide} (COC), a synthetic molecule, in OSCC cells. COC exhibits potent tumor-suppressive efficacy with IC50 values of 195 nM and 204 nM toward SCC2095 and SCC4 OSCC cells, respectively.

Anticancer activity of EMD37 against human head and neck cancer: Impact on apoptotic and inflammatory machineries.

Accumulating evidence emphasizes the tumorigenic role of epidermal growth factor receptor (EGFR) in head and neck cancer (HNC). Although cetuximab is the sole anti-EGFR approved by the Food and Drug Administration for treating HNC patients.its response rates are modest.

Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells.

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC.

FLT3 inhibitors and novel therapeutic strategies to reverse AML resistance: An updated comprehensive review.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in almost 30% of acute myeloid leukemia (AML) patients. Despite the initial clinical efficacy of FLT3 inhibitors, many treated AML patients with mutated FLT3 eventually relapse. This review critically discusses the opportunities and challenges of FLT3-targeted therapies and sheds light on their drug interactions as well as potential biomarkers.

SAR investigation and optimization of benzimidazole-based derivatives as antimicrobial agents against Gram-negative bacteria.

Antibiotic-resistant bacteria represent a serious threat to modern medicine and human life. Only a minority of antibacterial agents are active against Gram-negative bacteria. Hence, the development of novel antimicrobial agents will always be a vital need.

Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity.

Targeting endoplasmic reticulum (ER) stress presents a promising strategy in cancer therapy. We previously reported a series of 1,2,4-oxadiazole derivatives that induced the degradation of EGFR and c-Met which are implicated in tumorigenesis. Based on our previous SAR studies, herein, we report the discovery of EMD37, a novel 1,2,4-oxadiazole derivative, which demonstrated potent anticancer activity against NCI-60 cancer cell lines panel compared to its parent/lead compounds.

Induction of apoptosis using ATN as a novel Yes-associated protein inhibitor in human oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) represents a clinical challenge due to the lack of effective therapy to improve prognosis. Hippo/Yes-associated protein (YAP) signaling has emerged as a promising therapeutic target for squamous cell carcinoma treatment. In this study, we investigated the antitumor activity and underlying mechanisms of {[N-(4-(5-(3-(3-(4-acetamido-3-(trifluoromethyl)phenyl)ureido)phenyl)-1,2,4-oxadiazol-3-yl)-3-chlorophenyl)-nicotinamide]} (ATN), a novel YAP inhibitor, in OSCC cells.

Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML.

Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer.

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1).

Penicillin binding protein 2a: An overview and a medicinal chemistry perspective.

Antimicrobial resistance is an imminent threat worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the "superbug" family, manifesting resistance through the production of a penicillin binding protein, PBP2a, an enzyme that provides its transpeptidase activity to allow cell wall biosynthesis. PBP2a's low affinity to most β-lactams, confers resistance to MRSA against numerous members of this class of antibiotics.

Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway.

Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound ), we identified a closely related derivative, compound , which exhibited cogent antitumor activities while devoid of compound 's ability to promote EGFR/c-Met degradation. Compound acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1.

Development of benzimidazole-based derivatives as antimicrobial agents and their synergistic effect with colistin against gram-negative bacteria.

Gram-negative bacteria pose a distinctive risk worldwide, especially with the evolution of major resistance to carbapenems, fluoroquinolones and colistin. Therefore, development of new antibacterial agents to target Gram-negative infections is of utmost importance. Using phenotypic screening, we synthesized and tested thirty-one benzimidazole derivatives against E.

1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC.

Development of small-molecule agents with the ability to facilitate oncoprotein degradation has emerged as a promising strategy for cancer therapy. Since EGFR and c-Met are both implicated in oncogenesis and tumor progression, we initiated a screening program by using an in-house library to identify agents capable of inducing the concomitant suppression of EGFR and c-Met expression, which led to the identification of compound 1, a 1,2,4-oxadiazole derivative. Based on the scaffold of 1, we developed a series of derivatives to assess their efficacies in facilitating the downregulation of EGFR and c-Met, among which compound 48 represented the optimal agent.

A 5' AMP-Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma.

5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy.

Development of Potent Adenosine Monophosphate Activated Protein Kinase (AMPK) Activators.

Previously, we reported the identification of a thiazolidinedione-based adenosine monophosphate activated protein kinase (AMPK) activator, compound 1 (N-[4-({3-[(1-methylcyclohexyl)methyl]-2,4-dioxothiazolidin-5-ylidene}methyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide), which provided a proof of concept to delineate the intricate role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial-mesenchymal transition (EMT) in cancer cells. In this study, we used 1 as a scaffold to conduct lead optimization, which generated a series of derivatives. Analysis of the antiproliferative and AMPK-activating activities of individual derivatives revealed a distinct structure-activity relationship and identified 59 (N-(3-nitrophenyl)-N'-{4-[(3-{[3,5-bis(trifluoromethyl)phenyl]methyl}-2,4-dioxothiazolidin-5-ylidene)methyl]phenyl}urea) as the optimal agent.

Ligand design, synthesis and biological anti-HCV evaluations for genotypes 1b and 4a of certain 4-(3- & 4-[3-(3,5-dibromo-4-hydroxyphenyl)-propylamino]phenyl) butyric acids and 3-(3,5-dibromo-4-hydroxyphenyl)-propylamino-acetamidobenzoic acid esters.

4-(4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylamino]phenyl)-4-oxo-butyric acid (V), 4-(3- & 4-[N-1-carboxy-3-(3,5-dibromo-4-hydroxyphenyl)-3-oxo-propylaminophenyl]-2-aryl-4-oxo-butyric acids (Xa-e) and 4-(2-alkyl-2-[N-3-(3,5-dibromo-4-hydroxyphenyl)-1-carboxy-3-oxo-propylamino]acetamido) benzoate esters (XVa-e) were designed, synthesized and biologically evaluated as anti-HCV for genotypes 1b and 4a. The design was based on their docking scores with HCV NS3/4A protease-binding site of the genotype 1b (1W3C), which is conserved in the genotype 4a structure. The docking scores predicted that most of these molecules have higher affinity to the HCV NS3/4A enzyme more than Indoline lead.