Binding characteristics of pyrrole-scaffold hepatitis B virus capsid inhibitors and identification of novel potent compounds.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) are currently being evaluated in clinical trials as potential curative therapies for HBV. This study used in silico computational modeling to provide insights into the binding characteristics between the HBV core protein and two pyrrole-scaffold inhibitors, JNJ-6379 and GLP-26, both in the CAM-Normal (CAM-N) series. Molecular dynamics simulations showed that the pyrrole inhibitors displayed similar general binding-interaction patterns to NVR 3-778, another CAM-N, with hydrophobic interactions serving as the major driving force. However, consistent with their higher potency, the pyrrole inhibitors exhibited stronger nonpolar interactions with key residues in a solvent-accessible region as compared to NVR 3-778. This feature was facilitated by distinct hydrogen bond interactions of the pyrrole scaffold inhibitors with the residue 140 in chain B of the HBV core protein (L140B). Based on these findings, novel CAM-N compounds were designed to mimic the interaction with L140B residue while maximizing nonpolar interactions in the solvent-accessible region. Several 1H-pyrrole-2-carbonyl substituted pyrrolidine-based compounds with various hydrophobic side chains were synthesized and evaluated. Through analyses of the structure-activity and structure-druggability relations of a series of compounds, CU15 emerged as the most promising lead CAM-N compound, exhibiting sub-nanomolar potency and good pharmacokinetic profiles. Overall, the study demonstrated a practical approach to leverage computational methods for understanding key target binding features for rationale-based design, and for guiding the identification of novel compounds.

Micelle-Enabled One-Pot Guanidine Synthesis in Water Directly from Isothiocyanate using Hypervalent Iodine(III) Reagents under Mild Conditions.

In this work, we developed a one-pot synthesis of guanidine directly from isothiocyanate using DIB (diacetoxyiodobenzene) as a desulfurizing agent under micellar conditions in water. Our optimization study revealed that the use of 1 % TPGS-750-M as a surfactant with NaOH as an additive base at room temperature can convert a variety of isothiocyanates and amines into corresponding guanidines in excellent yields (69-95 %). This synthetic process in water can be applied to prepare guanidine at gram-scale quantity. Our aqueous micellar medium also demonstrated high reusability as the reaction can be performed for several cycles without losing its efficiency. The reaction is metal-free, utilizes water as solvent and practical (room temperature and open flask).

Microwave-Enhanced On-Water Amination of 2-Mercaptobenzoxazoles To Prepare 2-Aminobenzoxazoles.

In this work, we developed a catalyst-free amination of 2-mercaptobenzoxazoles on water under microwave irradiation. The product, 2-aminobenzoxazoles, was successfully produced via direct amination with various amines in moderate to high yields. The formal synthesis of Suvorexant, a medication for the treatment of insomnia, was accomplished using a developed amination process. The reaction was completed in an hour at 100-150 °C in a microwave reactor without the use of external catalyst or additive. Key benefits of this process include an on-water reaction, short reaction time, being scalable and catalyst-free, and use of 2-mercaptobenzoxazoles as an inexpensive starting material having low environmental impact in its preparation.