Identification of novel diarylpyrimidine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against wild-type and K103N mutant viruses.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role in combination antiretroviral therapy (cART). To further enhance their antiviral activity and anti-resistance properties, we developed a series of novel NNRTIs, by specifically targeting tolerant region I of the NNRTI binding pocket. Among them, compound 9t-2 displayed excellent anti-HIV-1 potency against wild-type and prevalent mutant strains with EC values between 0.

Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles.

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC values ranging from 0.024 to 0.

Discovery of diarylpyrimidine derivatives bearing piperazine sulfonyl as potent HIV-1 nonnucleoside reverse transcriptase inhibitors.

HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions.

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators.

HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, exhibited moderate anti-HIV-1 activity with an EC value of 5.

The current progress in the use of boron as a platform for novel antiviral drug design.

Introduction: Boron has attracted extensive interest due to several FDA-approved boron-containing drugs and other pharmacological agents in clinical trials. As a semimetal, it has peculiar biochemical characteristics which could be utilized in designing novel drugs against drug-resistant viruses. Emerging and reemerging viral pandemics are major threats to human health.

Anti-Proliferative Effect of Potential LSD1/CoREST Inhibitors Based on Molecular Dynamics Model for Treatment of SH-SY5Y Neuroblastoma Cancer Cell Line.

Background: Lysine-specific demethylase is a demethylase enzyme that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH2 from the demethylation process.

Perception, knowledge and attitude towards influenza vaccine during COVID-19 pandemic in Jordanian population.

Introduction: Seasonal influenza is considered as one of the major causes of morbidity and mortality worldwide. This needs solutions to decrease burdens on the healthcare systems especially during the Coronavirus Disease (COVID-19) pandemic. Population knowledge, perception and attitude towards influenza vaccine during COVID-19 pandemic could have a positive impact to decrease mortality, morbidity and burdens on the healthcare system.

Design, synthesis, and mechanistic investigations of phenylalanine derivatives containing a benzothiazole moiety as HIV-1 capsid inhibitors with improved metabolic stability.

Further clinical development of PF74, a lead compound targeting HIV-1 capsid, is impeded by low antiviral activity and inferior metabolic stability. By modifying the benzene (region I) and indole of PF74, we identified two potent compounds (7m and 7u) with significantly improved metabolic stability. Compared to PF74, 7u displayed greater metabolic stability in human liver microsomes (HLMs) with half-life (t) 109-fold that of PF74.

Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors.

HIV-1 capsid (CA) plays indispensable and multiple roles in the life cycle of HIV-1, become an attractive target in antiviral therapy. Herein, we report the design, synthesis, and mechanism study of a novel series of dimerized phenylalanine derivatives as HIV-1 capsid inhibitors using 2-piperazineone or 2,5-piperazinedione as a linker. The structure-activity relationship (SAR) indicated that dimerized phenylalanines were more potent than monomers of the same chemotype.

Design, synthesis, and antiviral evaluation of novel piperidine-substituted arylpyrimidines as HIV-1 NNRTIs by exploring the hydrophobic channel of NNIBP.

Herein, alkenylpiperidine and alkynylpiperidine moieties were introduced into the left wing of DAPYs (diarylpyrimidines) to explore the new site of the NNIBP (non-nucleoside inhibitor binding pocket) protein-solvent interface region via the structure-based drug design strategy. All the synthesized compounds displayed nanomolar to submicromolar activity against WT (wild-type) HIV-1. Among all, compound FT1 (EC = 19 nM) was found to be the most active molecule, which is better than NVP (EC = 0.

Discovery of Novel Dihydrothiopyrano[4,3-]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles.

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3-]pyrimidine derivatives were rationally designed scaffold hopping and molecular hybridization strategies. Notably, compound yielded exceptionally potent antiviral activities (EC = 4.44-54.

Comparative QM/MM Molecular Dynamics and Umbrella Sampling Simulations: Interaction of the Zinc-Bound Intermediate Gem-Diolate Trapoxin A Inhibitor and Acetyl-l-lysine Substrate with Histone Deacetylase 8.

Targeting the genetic material without destruction is a priority to develop safe anticancer drugs. Histone deacetylase 8 (HDAC8), which is proved to be involved in carcinogenesis, is an enzyme associated with the chromatin for post-translational deacetylation of acetylated lysine. In this study, HDAC8 co-crystallized with the intermediate state tetrapeptide Trapoxin A (TA) inhibitor and the holoenzyme are utilized to find their conformational ensembles.

Novel and anti- effects of pomegranate peel ethanol extract.

Background And Aim: Interest in plants with antimicrobial properties has been revived due to emerging problems associated with using antibiotics to eradicate . Accordingly, this study aims to assess the antibacterial effects of and the possible synergistic effect of its extract along with metronidazole against .

Materials And Methods: Pomegranate peel ethanol extracts (PPEE) was tested against a control strain of (NCTC 11916) and in female Wistar rats.

Discovery and optimizing polycyclic pyridone compounds as anti-HBV agents.

Introduction: Hepatitis B disease is caused by the hepatitis B virus (HBV), which is a DNA virus that belongs to the Hepadnaviridae family. It is a considerable health burden, with 257 million active cases globally. Long-standing infection may create a fundamental cause of liver disease and chronic infections, including cirrhosis, hepatocellular, and carcinoma liver failure.

Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities.

The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound , which exhibited anti-HIV-1 activity 5.

RNA knockdown by synthetic peptidyl-oligonucleotide ribonucleases: behavior of recognition and cleavage elements under physiological conditions.

Sequence-specific ribonucleases are not found in nature. Absolute sequence selectivity in RNA cleavage normally requires multi-component complexes that recruit a guide RNA or DNA for target recognition and a protein-RNA assembly for catalytic functioning (e.g.

Discovery of novel "Dual-site" binding oseltamivir derivatives as potent influenza virus neuraminidase inhibitors.

From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH position of oseltamivir.

Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors.

The HIV-1 capsid (CA) protein plays crucial roles in both early and late stages of the viral life cycle, which has intrigued researchers to target it to develop anti-HIV drugs. Accordingly, in this research, we report the design, synthesis and biological evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors using the Cu(I)-catalyzed azide and alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. Among this series of inhibitors, compound displayed a remarkable anti-HIV activity (EC = 2.

Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities.

HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74, discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer.

Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016-2019).

: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insufficient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion. : In this review, the authors addressed the patent applications (2016-2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents.

Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines.

Background: Breast cancer is one of the most lethal types of cancer in women worldwide. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Previously, we have used quantitative structure activity relationship QSAR equations and their associated pharmacophore models to screen for new promising HER2 structurally diverse inhibitory leads which were tested against HER2-overexpressing SKOV3 ovarian cancer cell line.

The effect of ferrous ions, calcium ions and citric acid on absorption of ciprofloxacin across caco-2 cells: practical and structural approach.

Objective: To study the potential influence of selected metal ions on absorption (and hence oral bioavailability of ciprofloxacin (Cipro) in presence and absence of a competing ligand.

Significance: The presence of metal ions together with Cipro results in complexes exhibiting a decreased bioavailability. Attempts were made to better understand the mechanism of decreased Cipro bioavailability in the presence of metals such as calcium and ferrous ions, and a small-sized ligand citric acid (CitA).

Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket.

Exploring the Active Center of the LSD1/CoREST Complex by Molecular Dynamics Simulation Utilizing Its Co-crystallized Co-factor Tetrahydrofolate as a Probe.

Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically.

Comparative Molecular Dynamics Simulation of Aggregating and Non-Aggregating Inhibitor Solutions: Understanding the Molecular Basis of Promiscuity.

The presence of false positives in enzyme inhibition assays is a common problem in early drug discovery, especially for compounds that form colloid aggregates in solution. The molecular basis of these aggregates could not be thoroughly explored because of their transient stability. In this study we conducted comparative molecular dynamics (MD) simulations of miconazole, a strong aggregator, and fluconazole, a known non-aggregator.