Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 350
Filter
1.
J Enzyme Inhib Med Chem ; 39(1): 2402988, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39297697

ABSTRACT

Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects: one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound 6a being most effective (IC50 values of 1.23 and 1.37 µM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound 26a (IC50 of 1.56 µM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.


Subject(s)
Dose-Response Relationship, Drug , Inflammation , Neutrophils , Proto-Oncogene Proteins c-akt , Neutrophils/drug effects , Neutrophils/metabolism , Humans , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Structure-Activity Relationship , Molecular Structure , Inflammation/drug therapy , Inflammation/metabolism , Drug Discovery , Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis
2.
Article in English | MEDLINE | ID: mdl-39225209

ABSTRACT

BACKGROUND: Previous studies have reported that the cGMP-specific PDE5 isozyme is overexpressed in colon adenomas and adenocarcinomas and essential for colon cancer cell proliferation, while PDE5 selective inhibitors (e.g., sildenafil) have been reported to have cancer chemopreventive activity. AIM: This study aimed to determine the anticancer activity of a novel PDE5 inhibitor, RF26, using colorectal cancer (CRC) cells and the role of PDE5 in CRC tumor growth in vivo. OBJECTIVE: The objective of this study was to characterize the anticancer activity of a novel celecoxib derivative, RF26, in CRC cells previously reported to lack COX-2 inhibition but have potent PDE5 inhibitory activity. METHODS: Anticancer activity of RF26 was studied using human CRC cell lines. Its effects on intracellular cGMP levels, cGMP-dependent protein kinase (PKG) activity, ß-catenin levels, TCF/LEF transcriptional activity, cell cycle distribution, and apoptosis were measured. CRISPR/cas9 PDE5 knockout techniques were used to determine if PDE5 mediates the anticancer activity of RF26 and validate PDE5 as a cancer target. RESULTS: RF26 was appreciably more potent than celecoxib and sildenafil to suppress CRC cell growth and was effective at concentrations that increased intracellular cGMP levels and activated PKG signaling. RF26 suppressed ß-catenin levels and TCF/LEF transcriptional activity and induced G1 cell cycle arrest and apoptosis within the same concentration range. CRISPR/cas9 PDE5 knockout CRC cells displayed reduced sensitivity to RF26, proliferated slower than parental cells, and failed to establish tumors in mice. CONCLUSION: Further evaluation of RF26 for the prevention or treatment of cancer and studying the role of PDE5 in tumorigenesis are warranted.

3.
J Control Release ; 373: 583-598, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39047872

ABSTRACT

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo, with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications.


Subject(s)
Fatty Acids , Receptors, CXCR4 , Humans , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Animals , Fatty Acids/chemistry , Cell Line, Tumor , Structure-Activity Relationship , Molecular Dynamics Simulation , Drug Stability , Lipopeptides/chemistry , Lipopeptides/pharmacology , Female
4.
Future Med Chem ; 16(12): 1239-1254, 2024.
Article in English | MEDLINE | ID: mdl-38989990

ABSTRACT

Aim: Chemoresistance in cancer challenges the classical therapeutic strategy of 'one molecule-one target'. To combat this, multi-target therapies that inhibit various cancer-relevant targets simultaneously are proposed. Methods & results: We introduce 5-hydroxybenzothiophene derivatives as effective multi-target kinase inhibitors, showing notable growth inhibitory activity across different cancer cell lines. Specifically, compound 16b, featuring a 5-hydroxybenzothiophene hydrazide scaffold, emerged as a potent inhibitor, displaying low IC50 values against key kinases and demonstrating significant anti-cancer effects, particularly against U87MG glioblastoma cells. It induced G2/M cell cycle arrest, apoptosis and inhibited cell migration by modulating apoptotic markers. Conclusion: 16b represents a promising lead for developing new anti-cancer agents targeting multiple kinases with affinity to the hydroxybenzothiophene core.


[Box: see text].


Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors , Thiophenes , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Thiophenes/pharmacology , Thiophenes/chemistry , Thiophenes/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Apoptosis/drug effects , Cell Proliferation/drug effects , Structure-Activity Relationship , Cell Line, Tumor , Cell Movement/drug effects , Molecular Structure
5.
Cancers (Basel) ; 16(11)2024 May 27.
Article in English | MEDLINE | ID: mdl-38893153

ABSTRACT

Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

6.
Neurol Genet ; 10(3): e200156, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38784058

ABSTRACT

Background and Objectives: The endoplasmic reticulum (ER) membrane protein complex is a conserved multisubunit transmembrane complex that enables energy-independent insertion of newly synthesized membrane proteins into ER membranes, mediating protein folding, phospholipid transfer from ER to mitochondria, and elimination of misfolded proteins. The first subunit of EMC (EMC1) is encoded by EMC1. Both monoallelic de novo and biallelic EMC1 variants have been identified to cause cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [OMIM #616875]. Eight families with biallelic EMC1 variants and CAVIPMR have been reported. Here, we describe 8 individuals from 5 Kuwaiti families from the same tribe, with the previously reported homozygous pathogenic missense EMC1 variant [c.245C>T:p.(Thr82Met)] and CAVIPMR. Methods: Proband exome sequencing was performed in 3 families, while targeted molecular testing for EMC1 [c.245C>T:p.(Thr82Met)] variant was performed in the other 2 families based on strong clinical suspicion and tribal origin. Sanger sequencing confirmed variant segregation with disease in all families. Results: We identified 8 individuals from 5 Kuwaiti families with the homozygous pathogenic EMC1 variant [c.245C>T:p.(Thr82Met)] previously reported in a Turkish family with CAVIPMR. The variant was absent from Kuwait Medical Genetic Center database, thus unlikely to represent a population founder allelic variant. The average age at symptom onset was 11 weeks, with all families reporting either visual abnormalities, hypotonia, and/or global developmental delay (GDD) as the presenting features. Shared clinical features included GDD (8/8), microcephaly (8/8), truncal hypotonia (8/8), visual impairment (7/7), and failure to thrive (7/7). Other common features included hyperreflexia (5/6; 83%), peripheral hypertonia (3/5; 60%), dysmorphism (3/6; 50%), epilepsy (4/8; 50%), and chorea (3/8; 36%). Brain imaging showed cerebellar atrophy in 4/7 (57%) and cerebral atrophy in 3/6 (50%) individuals. Discussion: The presence of exact biallelic homozygous EMC1 variant in 5 Kuwaiti families from the same tribe suggests a tribal founder allelic variant. The clinical features in this study are consistent with the phenotypic spectrum of EMC1-associated CAVIPMR in previous reports. The presence of chorea, first noted in this study, further expands the phenotypic spectrum. Our findings emphasize the importance of targeted EMC1 variant [c.245C>T:p.(Thr82Met)] testing for infants from affected tribe who present with visual impairment, GDD, and hypotonia.

7.
Curr Org Synth ; 2024 May 06.
Article in English | MEDLINE | ID: mdl-38712369

ABSTRACT

In this work, a series of novel 3-(halophenyl)-1-phenyl-1H-pyrazole moieties have been synthesized. Their structures were characterized by IR, NMR, and MS spectroscopy, and the corresponding antitumor properties were also studied. OBJECTIVES: This study aimed to synthesize a series of new 3-(halophenyl)-1-phenyl-1Hpyrazole moieties and survey the antitumor properties of these compounds. MATERIALS AND METHODS: 3-(halophenyl)-1-phenyl-1H-pyrazoles (4a-j) were prepared by reaction of phenyl hydrazine (3) with different halogen aromatic aldehydes (1a-j) and malononitrile (2) in C2H5OH and piperidine. The reaction took place under microwave irradiation settings for two minutes at140°C. RESULTS: Three human cancer cell lines were used as in vitro test subjects for compounds 4a - j. Three cell lines from mammals HeLa (a cell line for human cervical cancer), MCF-7 (a cell line for human breast cancer), and PC-3 (a cell line for human prostate cancer), all with 5- fluorouracil as the standard reference drug were used. CONCLUSION: A series of novel 3-(halophenyl)-1-phenyl-1H-pyrazoles were synthesized in this work. All substances had their anticancer properties assessed.

8.
Sci Rep ; 14(1): 9862, 2024 04 29.
Article in English | MEDLINE | ID: mdl-38684707

ABSTRACT

The process of creating a series of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-q) involved reacting 6-methoxynaphthalen-2-ol (1), the appropriate aromatic aldehydes (2a-q), and malononitrile (3) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1H-benzo[f]chromene-2,8-dicarbonitrile (6a, d, e) was unsuccessful when 6-cyanonaphthalen-2-ol (5) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives (4 m, i, k) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br (4c, e) and a double bromine at 3,5-positions with a single methoxy group at 2-position (4n), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated (4a, b, d, f), dihalogenated (4 g, h, j, l) or trisubstituent phenyl ring (4o, p, q). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives (4a-f, g-q) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g, revealing bactericidal effects. Lastly, SAR and molecular docking were studied.


Subject(s)
Antineoplastic Agents , Microbial Sensitivity Tests , Pyrans , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Pyrans/pharmacology , Pyrans/chemistry , Pyrans/chemical synthesis , Cell Line, Tumor , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Molecular Docking Simulation , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Structure-Activity Relationship , Escherichia coli/drug effects
9.
Arch Pharm (Weinheim) ; 357(6): e2400020, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38478964

ABSTRACT

Haspin and Clk4 are both understudied protein kinases (PKs), offering potential targets for the development of new anticancer agents. Thus, the identification of new inhibitors targeting these PKs is of high interest. However, the inhibitors targeting haspin or Clk4 developed to date show a poor selectivity profile over other closely related PKs, increasing the risk of side effects. Herein, we present two newly developed N1-benzyolated 5-(4-pyridinyl)indazole-based inhibitors (18 and 19), derived from a newly identified indazole hit. These inhibitors exhibit an exceptional inhibitory profile toward haspin and/or Clk4. Compound 18 (2-acetyl benzoyl) showed a preference to inhibit Clk4 and haspin over a panel of closely related kinases, with sixfold selectivity for Clk4 (IC50 = 0.088 and 0.542 µM, respectively). Compound 19 (4-acetyl benzoyl) showed high selectivity against haspin over the common off-target kinases (Dyrks and Clks) with an IC50 of 0.155 µM for haspin. Molecular docking studies explained the remarkable selectivity of 18 and 19, elucidating how the new scaffold can be modified to toggle between inhibition of haspin or Clk4, despite the high homology of the ATP-binding sites. Their distinguished profile allows these compounds to be marked as interesting chemical probes to assess the selective inhibition of haspin and/or Clk4.


Subject(s)
Indazoles , Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Protein-Tyrosine Kinases , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Indazoles/pharmacology , Indazoles/chemistry , Indazoles/chemical synthesis , Humans , Structure-Activity Relationship , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Molecular Structure , Molecular Docking Simulation , Dose-Response Relationship, Drug , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis
10.
Bioorg Chem ; 145: 107244, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38428284

ABSTRACT

Complications of the worldwide use of non-steroidal anti-inflammatory drugs (NSAIDs) sparked scientists to design novel harmless alternatives as an urgent need. So, a unique hybridization tactic of quinoline/pyrazole/thioamide (4a-c) has been rationalized and synthesized as potential COX-2/15-LOX dual inhibitors, utilizing relevant reported studies on these pharmacophores. Moreover, we extended these preceding hybrids into more varied functionality, bearing crucial thiazole scaffolds(5a-l). All the synthesized hybrids were evaluatedin vitroas COX-2/15-LOX dual inhibitors. Initially, series4a-cexhibited significant potency towards 15-LOX inhibition (IC50 = 5.454-4.509 µM) compared to meclofenamate sodium (IC50 = 3.837 µM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates 5a-ldisclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids5d(IC50 = 0.239 µM, SI = 8.95), 5h(IC50 = 0.234 µM, SI = 20.35) and 5l (IC50 = 0.201 µM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC50 = 0.512 µM, SI = 4.28). In addition, the most potentcompounds, 4a, 5d, 5h, and 5l have been elected for further in vivoevaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds5d, 5h, and 5l decreased serum inflammatory markers including oxidative biomarkersiNO, and pro-inflammatory mediators cytokines like TNF-α, IL-6, and PGE. Ulcerogenic liability for tested compounds demonstrated obvious gastric mucosal safety. Furthermore, a histopathological study for compound 5l suggested a confirmatory comprehensive safety profile for stomach, kidney, and heart tissues. Docking and drug-likeness studies offered a good convention with the obtained biological investigation.


Subject(s)
Cyclooxygenase 2 Inhibitors , Quinolines , Rats , Animals , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/therapeutic use , Cyclooxygenase 2/metabolism , Celecoxib/therapeutic use , Cyclooxygenase 1/metabolism , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase Inhibitors/therapeutic use , Molecular Docking Simulation , Anti-Inflammatory Agents, Non-Steroidal , Quinolines/pharmacology , Quinolines/therapeutic use , Edema/chemically induced , Edema/drug therapy , Structure-Activity Relationship , Molecular Structure
11.
Bioorg Chem ; 145: 107235, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38447464

ABSTRACT

Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N1 of the indazole ring with m-hydroxyphenyl acetic acid yielded compound 21 with an IC50 value of 78 nM against haspin. This compound showed a meaningful selectivity over 15 of the most common off-targets, including Clk 1-3 and Dyrk1A, 1B, and 2. The most potent haspin inhibitors 5 and 21 effectively inhibited the growth of the NCI-60 cancer cell lines, further emphasizing the success of our scaffold as a new selective lead for the development of anti-cancer therapeutic agents.


Subject(s)
Antineoplastic Agents , Intracellular Signaling Peptides and Proteins , Intracellular Signaling Peptides and Proteins/metabolism , Indazoles/pharmacology , Protein Serine-Threonine Kinases , Histones/metabolism , Phosphorylation , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology
12.
Front Vet Sci ; 11: 1357947, 2024.
Article in English | MEDLINE | ID: mdl-38496314

ABSTRACT

Toxoplasmosis continues to be a prevalent parasitic zoonosis with a global distribution. This disease is caused by an intracellular parasite known as Toxoplasma gondii, and the development of effective novel drug targets to combat it is imperative. There is limited information available on the potential advantages of wheat germ oil (WGO) and propolis, both individually and in combination, against the acute phase of toxoplasmosis. In this study, acute toxoplasmosis was induced in Swiss albino mice, followed by the treatment of infected animals with WGO and propolis, either separately or in combination. After 10 days of experimental infection and treatment, mice from all groups were sacrificed, and their brains, uteri, and kidneys were excised for histopathological assessment. Additionally, the average parasite load in the brain was determined through parasitological assessment, and quantification of the parasite was performed using Real-Time Polymerase Chain Reaction targeting gene amplification. Remarkably, the study found that treating infected animals with wheat germ oil and propolis significantly reduced the parasite load compared to the control group that was infected but not treated. Moreover, the group treated with a combination of wheat germ oil and propolis exhibited a markedly greater reduction in parasitic load compared to the other groups. Similarly, the combination treatment effectively restored the histopathological changes observed in the brain, uterus, and kidney, and the scoring of these reported lesions confirmed these findings. In summary, the present results reveal intriguing insights into the potential therapeutic benefits of wheat germ oil and propolis in the treatment of acute toxoplasmosis.

13.
Sci Rep ; 14(1): 7589, 2024 03 31.
Article in English | MEDLINE | ID: mdl-38555345

ABSTRACT

P-glycoprotein (P-gp) imparts multi-drug resistance (MDR) on the cancers cell and malignant tumor clinical therapeutics. We report a class of newly designed and synthesized oxygen-heterocyclic-based pyran analogues (4a-l) bearing different aryl/hetaryl-substituted at the 1-postion were synthesized, aiming to impede the P-gp function. These compounds (4a-l) have been tested against cancerous PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines as well as non-cancerous HFL-1 and WI-38 cell lines to determine their anti-proliferative potency.The findings demonstrated the superior potency of 4a-c with 4-F, 2-Cl, and 3-Cl derivatives and 4h,g with 4-NO2, 4-MeO derivatives against PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines.Compounds 4a-c were tested for P-gp inhibition and demonstrated significant vigour against MCF-7/ADR cells with IC50 = 5.0-10.7 µM. The Rho123 accumulation assay showed that compounds 4a-c adequately inhibited P-gp function, as predicted. Furthermore, 4a or 4b administration resulted in MCF-7/ADR cell accumulation in the S phase, while compound 4c induced apoptosis by causing cell cycle arrest at G2/M. The molecular docking was applied to understand the likely modes of action and guide us in the rational design of more potent analogs. The investigate derivatives showed their good binding potential for p-gp active site with excellent docking scores and interactions. Finally, the majority of investigated derivatives 4a-c derivatives showed high oral bioavailability, but they did not cross the blood-brain barrier. These results suggest that they have favorable pharmacokinetic properties. Therefore, these compounds could serve as leads for designing more potent and stable drugs in the future.


Subject(s)
Antineoplastic Agents , Oxygen , Humans , MCF-7 Cells , Oxygen/metabolism , Molecular Docking Simulation , Drug Resistance, Neoplasm , Drug Resistance, Multiple , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Doxorubicin/pharmacology
14.
Eur J Med Chem ; 269: 116266, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38490063

ABSTRACT

In neurodegenerative diseases, using a single molecule that can exert multiple effects to modify the disease may have superior activity over the classical "one molecule-one target" approach. Herein, we describe the discovery of 6-hydroxybenzothiazol-2-carboxamides as highly potent and selective MAO-B inhibitors. Variation of the amide substituent led to several potent compounds having diverse side chains with cyclohexylamide 40 displaying the highest potency towards MAO-B (IC50 = 11 nM). To discover new compounds with extended efficacy against neurotoxic mechanisms in neurodegenerative diseases, MAO-B inhibitors were screened against PHF6, R3 tau, cellular tau and α-synuclein (α-syn) aggregation. We identified the phenethylamide 30 as a multipotent inhibitor of MAO-B (IC50 = 41 nM) and α-syn and tau aggregation. It showed no cytotoxic effects on SH-SY5Y neuroblastoma cells, while also providing neuroprotection against toxicities induced by α-syn and tau. The evaluation of key physicochemical and in vitro-ADME properties revealed a great potential as drug-like small molecules with multitarget neuroprotective activity.


Subject(s)
Neuroblastoma , Neurodegenerative Diseases , Humans , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Neuroprotection , Monoamine Oxidase/metabolism , Structure-Activity Relationship
15.
Bioorg Chem ; 145: 107228, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38422592

ABSTRACT

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.


Subject(s)
Antineoplastic Agents , Triple Negative Breast Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Apoptosis , Cell Line, Tumor , Cell Proliferation , CSK Tyrosine-Protein Kinase/metabolism , Drug Screening Assays, Antitumor , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , src-Family Kinases , Structure-Activity Relationship , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology
16.
Arch Pharm (Weinheim) ; 357(4): e2300656, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38304944

ABSTRACT

Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering the market and the persistent rise in multidrug resistance. Here, we describe a new class of potent antibacterial agents based on a 5-aryl-N2,N4-dibutylpyrimidine-2,4-diamine scaffold. Structural optimization focused on the 5-aryl moiety and the bioisosteric replacement of the side chain linker atom. Screening of the synthesized compounds focused on a panel of bacterial strains, including gram-positive Staphylococcus aureus strains (Newman MSSA, methicillin- and vancomycin-resistant), and the gram-negative Escherichia coli (ΔAcrB strain). Several compounds showed broad-spectrum antibacterial activity with compound 12, bearing a 4-chlorophenyl substituent, being the most potent among this series of compounds. This frontrunner compound revealed a minimum inhibitory concentration (MIC) value of 1 µg/mL against the S. aureus strain (Mu50 methicillin-resistant S. aureus/vancomycin-intermediate S. aureus) and an MIC of 2 µg/mL against other tested strains. The most potent derivatives were further tested against a wider panel of bacteria and evaluated for their cytotoxicity, revealing further potent activities toward Streptococcus pneumoniae, Enterococcus faecium, and Enterococcus faecalis. To explore the mode of action, compound 12 was tested in a macromolecule inhibition assay. The obtained data were supported by the safety profile of compound 12, which possessed an IC50 of 12.3 µg/mL against HepG2 cells. The current results hold good potential for a new class of extended-spectrum antibacterial agents.


Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Staphylococcus aureus , Structure-Activity Relationship , Bacteria , Pyrimidines/pharmacology , Microbial Sensitivity Tests
17.
J Med Chem ; 66(22): 15189-15204, 2023 11 23.
Article in English | MEDLINE | ID: mdl-37940118

ABSTRACT

EPI-X4, a natural peptide CXCR4 antagonist, shows potential for treating inflammation and cancer, but its short plasma stability limits its clinical application. We aimed to improve the plasma stability of EPI-X4 analogues without compromising CXCR4 antagonism. Our findings revealed that only the peptide N-terminus is prone to degradation. Consequently, incorporating d-amino acids or acetyl groups in this region enhanced peptide stability in plasma. Notably, EPI-X4 leads 5, 27, and 28 not only retained their CXCR4 binding and antagonism but also remained stable in plasma for over 8 h. Molecular dynamic simulations showed that these modified analogues bind similarly to CXCR4 as the original peptide. To further increase their systemic half-lives, we conjugated these stabilized analogues with large polymers and albumin binders. These advances highlight the potential of the optimized EPI-X4 analogues as promising CXCR4-targeted therapeutics and set the stage for more detailed preclinical assessments.


Subject(s)
HIV Infections , HIV-1 , Humans , HIV-1/metabolism , Peptides/chemistry , Receptors, CXCR4/metabolism , Albumins/metabolism , Signal Transduction , Amines/metabolism
18.
Pharmaceuticals (Basel) ; 16(11)2023 Nov 11.
Article in English | MEDLINE | ID: mdl-38004458

ABSTRACT

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.

19.
Int J Mol Sci ; 24(19)2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37834474

ABSTRACT

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.


Subject(s)
Antineoplastic Agents , Lung Neoplasms , Humans , Structure-Activity Relationship , ErbB Receptors/metabolism , Cell Proliferation , Molecular Docking Simulation , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Mutation , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antimetabolites/pharmacology , Pyrimidines/pharmacology , Pyrimidines/chemistry , Molecular Structure , Cell Line, Tumor
20.
Pharmaceuticals (Basel) ; 16(9)2023 Sep 06.
Article in English | MEDLINE | ID: mdl-37765073

ABSTRACT

Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.

SELECTION OF CITATIONS
SEARCH DETAIL