Synthetic Naphthoquinone Inhibits Herpes Simplex Virus Type-1 Replication Targeting Na+, K+ ATPase.

Since 1970 acyclovir (ACV) has been the reference drug in treating herpes simplex virus (HSV) infections. However, resistant herpes simplex virus type 1 (HSV-1) strains have emerged, narrowing the treatment efficacy. The antiviral activity of classical Na+, K+ ATPase enzyme (NKA) inhibitors linked the viral replication to the NKA's activity. Herein, we evaluated the anti-HSV-1 activity of synthetic naphthoquinones, correlating their antiviral activity with NKA inhibition. We tested seven synthetic naphthoquinones initially at 50 µM on HSV-1-infected African green monkey kidney cells (VERO cells). Only one compound, 2-hydroxy-3-(2-thienyl)-1,4-naphthoquinone (AN-06), exhibited higher antiviral activity with a low cytotoxicity. AN-06 reduced the viral titer of 9 (log10) to 1.32 (log10) and decreased the steps of attachment and penetration. The addition of AN-06 up to 20 h postinfection (hpi) interfered with the viral cycle. The viral infection alone increases NKA activity 3 h postinfection (hpi), scaling up to 6 hpi. The addition of AN-06 in a culture infected with HSV-1 decreased NKA activity, suggesting that its antiviral action is linked to NKA inhibition. Also, docking results showed that this compound binds at the same site of NKA in which adenosine triphosphate (ATP) binds. AN-06 exhibited promising pharmacokinetic and toxicology properties. Thus, we postulate that AN-06 may be a good candidate for antiviral compounds with a mechanism of action targeting NKA activity.

Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches.

Chikungunya virus (CHIKV) is the etiological agent of the Chikungunya fever which has spread worldwide. Clinically, this disease may lead to prolonged incapacitating joint pain that can compromise remarkably the patients' quality of life. However, there are no licensed vaccines or specific drugs to fight this infection yet, making the search for novel therapies an imperative need. In this scenario, the CHIKV nsP2 protease emerged as an attractive therapeutic target once this protein plays a pivotal role in viral replication and pathogenesis. Hence, we investigated the structural basis for the inhibition of this enzyme by using molecular docking and dynamics simulations. Compounds with inhibitory activities against CHIKV nsP2 protease determined experimentally were selected from the literature. Docking studies with a set of stereoisomers showed that trans isomers, but not cis ones, bound close to the catalytic dyad which may explain isomerism requirements to the enzyme's inhibition. Further, binding mode analyses of other known inhibitors revealed highly conserved contacts between inhibitors and enzyme residues like N1011, C1013, A1046, Y1079, N1082, W1084, L1205, and M1242. Molecular dynamics simulations reinforced the importance of some of these interactions and pointed to nonpolar interactions as the main forces for inhibitors' binding. Finally, we observed that true inhibitors exhibited lower structural fluctuation, higher ligand efficiency and did not induce significant changes in protein correlated motions. Collectively, our findings might allow discerning true inhibitors from false ones and can guide drug development efforts targeting the nsP2 protease to fight CHIKV infections in the future.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Synthesis and evaluation of the cytotoxic activity of Furanaphthoquinones tethered to 1H-1,2,3-triazoles in Caco-2, Calu-3, MDA-MB231 cells.

Naphthoquinones and 1,2,3-triazoles are structural pharmacophore that is known to impart several cancer cells. This work shows a synthetic methodology to obtain hybrid molecules involving naphthoquinone and triazol scaffold as multiple ligands. A simple and efficient synthetic route was used to prepare a series of sixteen compounds being eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[1,2 b]furan-4,5-diones and eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[2,3-b]furan-4,9-diones. These compounds were tested in MDA-MB231, Caco-2 and Calu-3 human cancer cells, and among them 7a was the most selective compound on Caco-2 cells, the most sensitized cell line in this study. In silico study suggest that the blockage of topoisomerase I and IIα may be one of the mechanisms of action responsible for the cytotoxic effect of 7a in Caco-2 cells.

Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.

Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.