226 research outputs found
Identification of 2-(N-aryl-1,2,3-triazol-4-yl) quinoline derivatives as antitubercular agents endowed with InhA inhibitory activity
The spread of drug-resistant tuberculosis strains has become a significant economic burden globally. To tackle this challenge, there is a need to develop new drugs that target specific mycobacterial enzymes. Among these enzymes, InhA, which is crucial for the survival of Mycobacterium tuberculosis, is a key target for drug development. Herein, 24 compounds were synthesized by merging 4-carboxyquinoline with triazole motifs. These molecules were then tested for their effectiveness against different strains of tuberculosis, including M. bovis BCG, M. tuberculosis, and M. abscessus. Additionally, their ability to inhibit the InhA enzyme was also evaluated. Several molecules showed potential as inhibitors of M. tuberculosis. Compound 5n displayed the highest efficacy with a MIC value of 12.5 μg/mL. Compounds 5g, 5i, and 5n exhibited inhibitory effects on InhA. Notably, 5n showed significant activity compared to the reference drug Isoniazid. Molecular docking analysis revealed interactions between these molecules and their target enzyme. Additionally, the molecular dynamic simulations confirmed the stability of the complexes formed by quinoline-triazole conjugate 5n with the InhA. Finally, 5n underwent in silico analysis to predict its ADME characteristics. These findings provide promising insights for developing novel small compounds that are safe and effective for the global fight against tuberculosis
Metabolomic profile, anti-trypanosomal potential and molecular docking studies of <i>Thunbergia grandifolia</i>
Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves
Novel quinazoline-based sulfonamide derivative (3D) induces apoptosis in colorectal cancer by inhibiting JAK2–STAT3 pathway
Introduction: Colorectal cancer (CRC) is a major worldwide health problem owing to its high
prevalence and mortality rate. Developments in screening, prevention, biomarker, personalized
therapies and chemotherapy have improved detection and treatment. However, despite these
advances, many patients with advanced metastatic tumors still succumb to the disease. New
anticancer agents are needed for treating advanced stage CRC as most of the deaths occur due to
cancer metastasis. A recently developed novel sulfonamide derivative 4-((2-(4-(dimethylamino)
phenyl)quinazolin-4-yl)amino)benzenesulfonamide (3D) has shown potent antitumor effect;
however, the mechanism underlying the antitumor effect remains unknown.
Materials and methods: 3D-mediated inhibition on cell viability was evaluated by MTT and
real-time cell proliferation was measured by xCelligence RTDP instrument. Western blotting
was used to measure pro-apoptotic, anti-apoptotic proteins and JAK2-STAT3 phosphorylation.
Flow cytometry was used to measure ROS production and apoptosis.
Results: Our study revealed that 3D treatment significantly reduced the viability of human CRC
cells HT-29 and SW620. Furthermore, 3D treatment induced the generation of reactive oxygen
species (ROS) in human CRC cells. Confirming our observation, N-acetylcysteine significantly
inhibited apoptosis. This is further evidenced by the induction of p53 and Bax; release of cytochrome
c; activation of caspase-9, caspase-7 and caspase-3; and cleavage of PARP in 3D-treated cells. This
compound was found to have a significant effect on the inhibition of antiapoptotic proteins Bcl2 and
BclxL. The results further demonstrate that 3D inhibits JAK2–STAT3 pathway by decreasing the
constitutive and IL-6-induced phosphorylation of STAT3. 3D also decreases STAT3 target genes
such as cyclin D1 and survivin. Furthermore, a combination study of 3D with doxorubicin (Dox)
also showed more potent effects than single treatment of Dox in the inhibition of cell viability.
Conclusion: Taken together, these findings indicate that 3D induces ROS-mediated apoptosis
and inhibits JAK2–STAT3 signaling in CRC
Carbonic anhydrase inhibitors targeting metabolism and tumor microenvironment
The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed
Development of novel isatin thiazolyl-pyrazoline hybrids as promising antimicrobials in MDR pathogens
Microbial Multidrug Resistance (MDR) is an emerging global crisis. Derivatization of natural or synthetic
scaffolds is among the most reliable strategies to search for and obtain novel antimicrobial agents for
the treatment of MDR infections. Here, we successfully manipulated the synthetically flexible isatin
moieties to synthesize 22 thiazolyl-pyrazolines hybrids, and assessed their potential antimicrobial
activities in vitro against various MDR pathogens, using the broth microdilution calorimetric XTT
reduction method. We chose 5 strains to represent the major MDR microorganisms, viz: Methicillin
resistant S. aureus (MRSA), and Vancomycin-resistant E. faecalis (VRE) as Gram-positive bacteria;
Carbapenem-resistant K. pneumonia (CRKP), and Extended-spectrum beta-lactamase E. coli (ESBL-E), as
Gram-negative bacteria; and Fluconazole-resistant C. albicans (FRCA), as a yeast-like unicellular fungus.The cytotoxicity of compounds 9f and 10h towards mammalian lung fibroblast (MRC-5) cells demonstrated their potential satisfactory safety margin as represented by their relatively high IC50 values. The target compounds showed promising anti-MDR activities, suggesting they are potential leads for further development and in vivo studies
Development and Validation of High-Throughput Bioanalytical Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Quantification of Newly Synthesized Antitumor Carbonic Anhydrase Inhibitors in Human Plasma
In the present study, a sensitive and fully validated bioanalytical high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the quantitative determination of three newly synthesized carbonic anhydrases inhibitors (CAIs) with potential antitumor activity in human plasma. The analytes and the internal standard (IS) were extracted using 1.5 mL acetonitrile from only 450 µL aliquots of human plasma to achieve the desired protein precipitation. Chromatographic separations were achieved on Phenomenex Kinetex® C18 column (100 × 4.6 mm, 2.6 µm) using a binary gradient elution mode with a run time of less than 6 min. The mobile phase consisted of solvent (A): 0.1% formic acid in 50% methanol and solvent B: 0.1% formic acid in acetonitrile (30:70, v/v), pumped at a flow rate of 0.8 mL/min. Detection was employed using triple quadrupole tandem mass spectrometer (API 3500) equipped with an electrospray ionization (ESI) source in the positive ion mode. Multiple reaction monitoring (MRM) mode was selected for quantitation through monitoring the precursor-to-parent ion transition at m/z 291.9 → 173.0, m/z 396.9 → 225.1, m/z 388.9 → 217.0, and m/z 146.9 → 91.0 for AW-9a, WES-1, WES-2, and Coumarin (IS), respectively. Linearity was computed using the weighted least-squares linear regression method (1/x2) over a concentration range of 1–1000, 2.5–800, and 5–500 ng/mL for AW-9a, WES-1, and WES-2; respectively. The bioanalytical LC-MS/MS method was fully validated as per U.S. Food and Drug Administration (FDA) guidelines with all respect to linearity, accuracy, precision, carry-over, selectivity, dilution integrity, and stability. The proposed LC-MS/MS method was applied successfully for the determination of all investigated drugs in spiked human plasma with no significant matrix effect, which is a crucial cornerstone in further therapeutic drug monitoring of newly developed therapeutic agents
Novel thiazolidinone/thiazolo[3,2-a] benzimidazolone-isatin conjugates as apoptotic anti-proliferative agents towards breast cancer: One-pot synthesis and in vitro biological evaluation
In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a-n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a-d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50= 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study
Design, Synthesis, and Molecular Docking of 1-(1-(4-Chlorophenyl)-2-(phenylsulfonyl)ethylidene)-2-phenylhydrazine as Potent Nonazole Anticandidal Agent
1-(1-(4-Chlorophenyl)-2-(phenylsulfonyl)ethylidene)-2-phenylhydrazine (13) was designed and synthesized as potential nonazole anticandidal agent and precisely characterized by IR, 1H NMR, 13C NMR, and ESI-MS. The anti-Candida activity of 13 was evaluated against four Candida species (C. albicans, C. krusei, C. parapsilosis, and C. glabrata). Compound 13 displayed good anticandidal activities (MIC=0.39, 0.195, 0.39, and 1.56 μmol/mL, resp.) in comparison with that of the standard drug fluconazole (MIC=0.195, inactive, 1.56, and 1.56 μmol/mL, resp.) against C. albicans, C. krusei, C. parapsilosis, and C. glabrata, respectively. A molecular modeling of the newly synthesized compound 13 was built in order to investigate its mode of action towards the prospective target cytochrome P450-dependent enzyme lanosterol 14α-demethylase (PDB-code: 1EA1). The docking results showed a similar binding interaction of 13 and fluconazole at the active site of CYT P450 14α-sterol demethylase. Furthermore, compound 13 showed no cytotoxicity against normal human breast cell line MCF10A
Synthesis, Crystal Structure, and Biological Activity of cis/trans Amide Rotomers of (Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide
(Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide (2) was synthesized by the reaction of (Z)-3-hydrazonoindolin-2-one (1) with formic acid under reflux. The structure of 2 was characterized by IR, Mass, 1H NMR, and X-ray crystal structure determination. Interestingly, compound 2 appeared in DMSO-d6 as cis and trans amide rotomers in 25% and 75%, respectively. The X-ray analysis showed the Z geometrical isomer of 2 around –C=N– for cis and trans amide rotomers. The crystal of 2 belongs to monoclinic, space group P21/c, with a=4.5206 (1) Å, b=22.4747 (7) Å, c=17.3637 (5) Å, β=103.752 (1)°, Z=8, V=1713.57 (8) Å3, Dc=1.467 Mg m−3, μ=0.11 mm−1, F(000)=784, R=0.047, and wR=0.123 for 3798 observed reflections with I>2σ(I). Compound 2 exhibited a moderate activity in its antimicrobial evaluation against E. coli and P. aeruginosa and a good activity against S. aureus close to that of the standard drug ciprofloxacin. The in vitro anticancer activity of 2 was evaluated against two human tumor cell lines, namely, HepG2 hepatocellular carcinoma and MCF-7 breast cancer. HepG2 cancer cell line was more susceptible to compound 2 than MCF-7
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