Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA).

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities.

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives "5a-o". Results from the screening on A549 and MCF7 cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn't change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In light of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic indicators were studied.

An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review.

RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS's structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein's role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS-effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field's future.

Identification of 3-(5-cyano-6-oxo-pyridin-2-yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity.

New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.

Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights.

The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI50 levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explainthe biological activities of the most potent compound.

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors.

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations.

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.

Eriodictyol attenuates doxorubicin-induced nephropathy by activating the AMPK/Nrf2 signalling pathway.

Doxorubicin (DOX), an anthracycline chemotherapy, plays a prominent role in the treatment of various cancers. Unfortunately, its nephrotoxic effects limit its dosing and expose cancer survivors to increased morbidity and mortality. This study examined the nephroprotective effects of eriodictyol, a natural polyphenolic flavanone, in DOX-treated rats and the molecular pathways involved. Forty adult rats were divided into five groups (8/group): Control; eriodictyol (20 mg/kg/day); DOX (2.5 mg/kg, twice/week); DOX + Eriodictyol; and DOX + Eriodictyol + Compound C (CC), an AMPK inhibitor (0.2 mg/kg/day). Experiments continued for 21 days. Eriodictyol administration in DOX-treated rats reduced their fasting glucose levels and increased food intake, final body weight, and kidney weight, improved kidney function, prevented glomerular and tubular damage, and reduced collagen deposition and renal TGF-ß1 mRNA levels. Furthermore, eriodictyol reduced their renal levels of Bax, caspase-3, and cytochrome-c; and enhanced the levels of Bcl2. Noticeably, in the kidneys of both controls and DOX-treated rats, eriodictyol increased levels of phosphorylated-AMPK(Thr172) but not AMPK mRNA nor protein levels. Also, in the same two groups, eriodictyol increased mRNA and nuclear Nrf2 levels, and levels of glutathione, superoxide dismutase, catalase, and hemeoxygenase-1, but reduced the levels of malonaldehyde, TNF-α, and mRNA, total, and nuclear levels of NF-κB. All the detected nephroprotective effects and improvements in the levels of markers of oxidation and inflammation were prevented by coadministration of CC. In conclusion, the coadministration of eriodictyol and DOX alleviates DOX-induced renal damage. In renal tissues, eriodictyol is an AMPK activator and its nephroprotective antioxidant and anti-inflammatory effects are AMPK-dependent.

Sonophoresis mediated diffusion of caffeine loaded Transcutol® enriched cerosomes for topical management of cellulite.

The goal of this research was to augment the deposition of caffeine loaded Transcutol® enriched cerosomes (TECs) gel for efficient topical treatment of cellulite utilizing the sonophoresis technique. Caffeine-loaded TECs were prepared using thin film hydration method applying 23 factorial design to study the impact of different factors, each with two levels on the entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of the formulated TECs. The studied factors were cetyl trimethyl ammonium bromide (CTAB) amount (mg) (X1), phosphatidylcholine (PC) amount (mg) (X2), and Transcutol® amount (mg) (X3). Design-Expert® software was utilized to determine the optimum TECs formulation. Afterward, the optimum TECs formulation was loaded into a gel and subjected to extra investigations. The optimum TECs formulation was (TEC5) which was prepared using 10 mg of CTAB, 150 mg of PC, and 10 mg of Transcutol®. TEC5 presented EE% of 87.44 ± 0.14 %, PS of 308.60 ± 13.38 nm, PDI of 0.455 ± 0.030, and ZP of 50.20 ± 1.55 mV. TEC5 had a fiber-like morphology, with elongated tubules of ceramide. Further, the optimum TECs formulation showed a high stability profile. Moreover, an in vivo dermatokinetic study showed superior deposition of caffeine from TEC5 gel coupled with the sonophoresis on rat skin compared to TEC5 gel and caffeine gel. Moreover, the histopathological study of TEC5 on rat skin confirmed the non-irritant nature of TEC 5 gel mediated by ultrasonic waves through the skin. Overall, the outcomes exposed the obvious superiority of sonophoresis delivered TECs-gel for topical delivery of caffeine for cellulite management.

Phenotypic and Genotypic Analysis of Bacterial Pathogens Recovered from Patients Diagnosed with Fever of Unknown Origin in Egypt.

Fever of unknown origin (FUO) is a medical term describing fever that lasts for at least three weeks without a diagnosis being reached after extensive diagnostic evaluation. Therefore, this study aimed to identify the common pathogens causing FUO in patients admitted to Abbasia Fever Hospital in Egypt from January 2020 to December 2022, their antimicrobial susceptibility profiles, and associated resistance genes. The study also aimed to investigate the burden of multidrug-resistant (MDR) pathogens and the priority pathogens nominated by the World Health Organization (WHO) for posing the greatest threat to human health due to antibiotic resistance. During the study period, about 726 patients were diagnosed with FUO. After extensive investigations, the cause of the FUO was found to be infectious diseases in 479/726 patients (66.0%). Of them, 257 patients had positive bacterial cultures, including 202 Gram-negative isolates that comprised Klebsiella pneumoniae (85/202; 42.1%), Escherichia coli (71/202; 35.1%), Acinetobacter baumannii (26/202; 12.9%), and Pseudomonas aeruginosa (14/202; 6.9%) and 55 Gram-positive isolates, including Staphylococcus aureus (23/55; 41.8%), Streptococcus pneumoniae (7/55; 12.7%), and Enterococcus spp. (25/55; 45.5%). The MDR phenotype was shown by 68.3% and 65.5% of the Gram-negative and Gram-positive isolates, respectively. Carbapenem resistance (CR) was shown by 43.1% of the Gram-negative isolates. Of the 23 S. aureus isolates obtained from research participants, 15 (65.2%) were methicillin-resistant S. aureus (MRSA). A high-level aminoglycoside resistance (HLAR) phenotype was found in 52.0% of the Enterococcus sp. isolates. The PCR screening of resistance genes in the MDR isolates showed that blaOXA-48 was the most prevalent (84%) among the carbapenemase-coding genes, followed by blaVIM (9%) and then blaIMP (12%). The ESBL-coding genes blaTEM, blaCTX-M,aac(6')-Ib, and blaSHV, were prevalent in 100%, 93.2%, 85,% and 53.4% of the MDR isolates, respectively. This study updates the range of bacteria that cause FUO and emphasizes the burden of multidrug resistance and priority infections in the region. The obtained data is of relevant medical importance for the implementation of evidence-based antimicrobial stewardship programs and tailoring existing empirical treatment guidelines.