The first-in-class pyrazole-based dual InhA-VEGFR inhibitors towards integrated antitubercular host-directed therapy.

Several facets of the host response to tuberculosis have been tapped for clinical investigation, especially targeting angiogenesis mediated by VEGF signaling from infected macrophages. Herein, we rationalized combining the antiangiogenic effects of VEGFR-2 blockade with direct antitubercular InhA inhibition in single hybrid dual inhibitors as advantageous alternatives to the multidrug regimens. Inspired by expanded triclosans, the ether ligation of triclosan was replaced by rationalized linkers to assemble the VEGFR-2 inhibitors thematic scaffold. Accordingly, new series of 3-(p-chlorophenyl)-1-phenylpyrazole derivatives tethered to substituted ureas and their isosteres were synthesized, evaluated against Mycobacterium tuberculosis virulent cell line H37Rv, and assessed for their InhA inhibitory activities. The urea derivatives 8d and 8g exhibited the most promising antitubercular activity (MIC = 6.25 µg/mL) surpassing triclosan (MIC = 20 µg/mL) with potential InhA inhibition, thus identified as the study hits. Interestingly, both compounds inhibited VEGFR-2 at nanomolar IC50 (15.27 and 24.12 nM, respectively). Docking and molecular dynamics simulations presumed that 8d and 8g could bind to their molecular targets InhA and VEGFR-2 posing essential stable interactions shared by the reference inhibitors triclosan and sorafenib. Finally, practical LogP, Lipinski's parameters and in silico ADMET calculations highlighted their drug-likeness as novel leads in the arsenal against TB.

Cinnamon Oil-Loaded Nanoliposomes with Potent Antibacterial and Antibiofilm Activities.

Despite recent scientific advances, the global load of bacterial disease remains high and has been established against a backdrop of increasing antimicrobial resistance. Therefore, there is a pressing need for highly effective and natural antibacterial agents. In the present work, the antibiofilm effect provided by essential oils was evaluated. Of these, cinnamon oil extract showed potent antibacterial and antibiofilm activities against Staphylococcus aureus at an MBEC of 75.0 µg/mL. It was revealed that benzyl alcohol, 2-propenal-3-phenyl, hexadecenoic acid, and oleic acid were the major components of the tested cinnamon oil extract. In addition, the interaction between the cinnamon oil and colistin showed a synergistic effect against S. aureus. Cinnamon oil that had been combined with colistin was encapsulated by liposomes to enhance the essential oil's chemical stability, demonstrating a particle size of 91.67 nm, a PDI of 0.143, a zeta potential of -0.129 mV, and an MBEC of 50.0 µg/mL against Staphylococcus aureus. Scanning electron microscopy was employed to observe the morphological changes in the Staphylococcus aureus biofilm that was treated with the encapsulated cinnamon oil extract/colistin. As a natural and safe option, cinnamon oil exhibited satisfactory antibacterial and antibiofilm performance. The application of liposomes further improved the stability of the antibacterial agents and extended the essential oil release profile.

Nanoemulsion of Lavandula angustifolia Essential Oil/Gold Nanoparticles: Antibacterial Effect against Multidrug-Resistant Wound-Causing Bacteria.

Hospitalized patients are severely impacted by delayed wound healing. Recently, there has been a growing focus on enhancing wound healing using suitable dressings. Lavandula angustifolia essential oil (LEO) showed potential antibacterial, anti-inflammatory, and wound healing properties. However, the prepared gold nanoparticles possessed multifunctional properties. Consequently, the present investigation aimed to synthesize a novel nanosystem consisting of nano-Lavandula angustifolia essential oil and gold nanoparticles prepared through ultrasonic nanoemulsifying techniques in order to promote wound healing and combat bacterial infection. LEO showed potent antibacterial activity against Klebsiella pneumoniae, MRSA and Staphylococcus aureus with minimum inhibitory concentration (MIC) values of 32, 16 and 16 µg/mL, respectively, while exhibiting low activity against Proteus mirabilis. Interestingly, the newly formulated nano-gold/nano-Lavandula angustifolia penetrated the preformed P. mirabilis biofilm with a full eradication of the microbial cells, with MIC and MBEC (minimal biofilm eradication concentration) values reaching 8 and 16 µg/mL, respectively. The cytotoxic effect of the novel nanoformula was also assessed against WI-38 fibroblasts vero (normal) cells (IC50 = 0.089 mg/mL) while nano-gold and nano-Lavandula angustifolia showed higher results (IC50 = 0.529, and 0.209 mg/mL, respectively). Nano-gold/nano-Lavandula angustifolia formula possessed a powerful wound healing efficacy with a 96.78% wound closure. These findings revealed that nano-gold/nano-Lavandula angustifolia nanoemulsion can inhibit bacterial growth and accelerate the wound healing rate.

Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic fatal infection with no known treatment. The severity of the disease and the fast viral mutations forced the scientific community to search for potential solution. Here in the present manuscript, some benzofused1,2,3triazolesulfonamide hybrids were synthesized and evaluated for their anti- SARS-CoV-2 activity using in silico prediction then the most potent compounds were assessed using in-Vitro analysis. The in-Silico study was assessed against RNA dependent RNA polymerase, Spike protein S1, Main protease (3CLpro) and 2'-O-methyltransferase (nsp16). It was found that 4b and 4c showed high binding scores against RNA dependent RNA polymerase reached -8.40 and -8.75 â€‹kcal/mol, respectively compared to the approved antiviral (remdesivir -6.77 â€‹kcal/mol). Upon testing the binding score with SARS-CoV-2 Spike protein it was revealed that 4c exhibited the highest score (-7.22 â€‹kcal/mol) compared to the reference antibacterial drug Ceftazidime (-6.36 â€‹kcal/mol). Surprisingly, the two compounds 4b and 4c showed the highest binding scores against SARS-CoV-2 3CLpro (-8.75, -8.48 â€‹kcal/mol, respectively) and nsp16 (- 8.84 and - 8.89 â€‹kcal/mol, respectively) displaying many types of interaction with all the enzymes binding sites. The derivatives 4b and 4c were examined in vitro for their potential anti-SARS-CoV-2 and it was revealed that 4c was the most promising compound with IC50 reached 758.8108 â€‹mM and complete (100%) inhibition of the binding of SARS-CoV-2 virus to human ACE2 can be accomplished by using 0.01 â€‹mg.

Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-ß-lactamase inhibitors.

Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-ß-lactamases (MBLs), using Klebsiella pneumoniaeNDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5-16.4 µM) against NDM-1, IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment.

Exploiting spirooxindoles for dual DNA targeting/CDK2 inhibition and simultaneous mitigation of oxidative stress towards selective NSCLC therapy; synthesis, evaluation, and molecular modelling studies.

The unique structure of spirooxindoles and their ability to feature various pharmacophoric motifs render them privileged scaffolds for tailoring new multitarget anticancer agents. Herein, a stereoselective multicomponent reaction was utilized to generate a small combinatorial library of pyrazole-tethered spirooxindoles targeting DNA and CDK2 with free radical scavenging potential as an extra bonus. The designed spirooxindoles were directed to combat NSCLC via inducing apoptosis and alleviating oxidative stress. The series' absolute configuration was assigned by X-ray diffraction analysis. Cytotoxicity screening of the developed spirooxindoles against NSCLC A549 and H460 cells compared to normal lung fibroblasts Wi-38 revealed the sensitivity of A549 cells to the compounds and raised 6e and 6h as the study hits (IC50 ∼ 0.09 µM and SI > 3). They damaged DNA at 24.6 and 35.3 nM, and surpassed roscovitine as CDK2 inhibitors (IC50 = 75.6 and 80.2 nM). Docking and MDs simulations postulated their receptors binding modes. The most potent derivative, 6e, induced A549 apoptosis by 40.85% arresting cell cycle at G2/M phase, and exhibited antioxidant activity in a dose-dependent manner compared to Trolox as indicated by DPPH scavenging assay. Finally, in silico ADMET analysis predicted the drug-likeness properties of 6e.

Novel 1,2,3-Triazole-sulphadiazine-ZnO Hybrids as Potent Antimicrobial Agents against Carbapenem Resistant Bacteria.

Bacterial pneumonia is considered one of the most virulent diseases with high morbidity and mortality rates, especially in hospitalized patients. Moreover, bacterial resistance increased over the last decades which limited the therapy options to carbapenem antibiotics. Hence, the metallo-ß-lactamase-producing bacteria were deliberated as the most deadly and ferocious infectious agents. Sulphadiazine-ZnO hybrids biological activity was explored in vitro and in vivo against metallo-ß-lactamases (MBLs) producing Klebsiella pneumoniae. Docking studies against NDM-1 and IMP-1 MBLs revealed the superior activity of the 3a compound in inhibiting both MBLs enzymes in a valid reliable docking approach. The MBLs inhibition enzyme assay revealed the remarkable sulphadiazine-ZnO hybrids inhibitory effect against NDM-1 and IMP-1 MBLs. The tested compounds inhibited the enzymes both competitively and noncompetitively. Compound 3b-ZnO showed the highest antibacterial activity against the tested metallo-ß-lactamase producers with an inhibition zone (IZ) diameter reaching 43 mm and a minimum inhibitory concentration (MIC) reaching 2 µg/mL. Sulphadiazine-ZnO hybrids were tested for their in vitro cytotoxicity in a normal lung cell line (BEAS-2Bs cell line). Higher cell viability was observed with 3b-ZnO. Biodistribution of the sulphadiazine-ZnO hybrids in the lungs of uninfected rats revealed that both [124I]3a-ZnO and [124I]3b-ZnO hybrids remained detectable within the rats' lungs after 24 h of endotracheal aerosolization. Moreover, the residence duration in the lungs of [124I]3b-ZnO (t1/2 4.91 h) was 85.3%. The histopathological investigations confirmed that compound 3b-ZnO has significant activity in controlling bacterial pneumonia infection in rats.

1,2,3-Triazole-Benzofused Molecular Conjugates as Potential Antiviral Agents against SARS-CoV-2 Virus Variants.

SARS-CoV-2 and its variants, especially the Omicron variant, remain a great threat to human health. The need to discover potent compounds that may control the SARS-CoV-2 virus pandemic and the emerged mutants is rising. A set of 1,2,3-triazole and/or 1,2,4-triazole was synthesized either from benzimidazole or isatin precursors. Molecular docking studies and in vitro enzyme activity revealed that most of the investigated compounds demonstrated promising binding scores against the SARS-CoV-2 and Omicron spike proteins, in comparison to the reference drugs. In particular, compound 9 has the highest scoring affinity against the SARS-CoV-2 and Omicron spike proteins in vitro with its IC50 reaching 75.98 nM against the Omicron spike protein and 74.51 nM against the SARS-CoV-2 spike protein. The possible interaction between the synthesized triazoles and the viral spike proteins was by the prevention of the viral entry into the host cells, which led to a reduction in viral reproduction and infection. A cytopathic inhibition assay in the human airway epithelial cell line (Vero E6) infected with SARS-CoV-2 revealed the effectiveness and safety of the synthesized compound (compound 9) (EC50 and CC50 reached 80.4 and 1028.28 µg/mL, respectively, with a selectivity index of 12.78). Moreover, the antiinflammatory effect of the tested compound may pave the way to reduce the reported SARS-CoV-2-induced hyperinflammation.