Synthesis, X-Ray Crystal Structure, Hirshfeld Surface Analysis, and Molecular Docking Study of Novel Hepatitis B (HBV) Inhibitor: 8-Fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one

Abstract

A method for the synthesis of 8-fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido [5,4-b]indol-4-one has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single-crystal X-ray analysis has revealed that it exists in a monoclinic P2 1 /n space group, with one molecule in the asymmetric part of the unit cell, a = 16.366(3) Å, b = 6.0295(14) Å, c = 21.358(4) Å, β = 105.21(2) • , V = 2033.7(7) Å 3 and Z = 4. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. Molecular docking studies have evaluated the investigated compound as a new inhibitor of hepatitis B. Testing for anti-hepatitis B virus activity has shown that this substance has in vitro nanomolar inhibitory activity against Hepatitis B virus (HBV). under investigation contain nitrogen heterocycles, and of these, 1H-indoles and pyrimidin-4(3H)-ones form a very substantial type of compounds. These heterocycles have the "privileged" indole framework which is commonly found in natural products and pharmaceutical drugs [7][8][9][10][11][12]. Pyrimidoindole moieties [13][14][15] are important structural motifs which are found in numerous pharmaceutically active compounds. They have revealed a wide range of high biological activity, such as antihypertensive and anti-inflammatory [16], anti-asthma [17,18], and act as α1-adrenergic receptor ligands or A1 adenosine receptor antagonists [19], potential tyrosine kinases (PTK) inhibitors, CFR1 and neuropeptide Y receptor ligands [20]. Despite the large spectrum of biological activity of these moieties, this range can be supplemented by introducing certain functional groups. Therefore, it is of substantial interest to develop efficient methods for the synthesis of such structures and their derivatives.In a continuation of our efforts to obtain new HBV inhibitors for treatment and prevention of human HBV infections [21,22], we initiated the design, synthesis, and anti-hepatitis B virus activity testing of a new 8-fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido [5,4-b] indol-4-one. Single-crystal X-ray analysis and different spectroscopic techniques assured the assigned chemical structure of the title compound. In addition, molecular docking simulations and study were also executed for the title compound. Results and DiscussionIn frames of the development of a platform for biologically active compound libraries, design for actual biotargets, including platform testing on the example of the invention and preparation of candidate libraries for HBV treatment designed as inhibitors of viral penetration and assembly of viral core particles, we have carried out a pilot in vitro screening of a series of new compounds. At the first stage of the cytotoxicity pilot screening, all the potential inhibitors of viral infection were studied, of which about 1000 showed cytotoxicity over 50% at 10 µM. A...

Preface of the Special Issue “Pharmaceutical Crystals”

“…Molecular docking is an emerging topic for pharmaceutical crystal study. Ivashchenko et al reported the crystal structure of a new biologically active molecule, which was also investigated as a new inhibitor of hepatitis B in a molecular docking study [9]. This substance has in vitro nanomolar inhibitory activity against the hepatitis B virus (HBV).…”

Crystal structure, Hirshfeld analysis and a molecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate

“…Heterocyclic homologues of 2H-1,2,6-thiadiazine-1,1-dioxides are inhibitors of human cytomegalovirus (Martínez et al, 2003), Cruzi triposome (Á lvarez et al, 2010) and diuretics (Goya et al, 1992). In a continuation of our efforts to obtain new HBV inhibitors for the treatment and prevention of human HBV infections (Ivachtchenko et al, 2019;Ivashchenko et al, 2019;Kovalenko et al, 2019), we initiated the design, synthesis, and anti-hepatitis B virus activity testing of the new 2H-1,2,6thiadiazine 1,1-dioxide derivative, ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate (3).…”

Synthesis, Single Crystal X-Ray Analysis, Prediction and Study of Pharmacological Activity of 4-(1H-Benzo[d]imidazol-2-yl)-1-Phenyl-1H-1,2,3-triazol-5-Amine and Its Solvates

“…The biological activity of compound 3 was studied using an experimental in vitro hepatitis B virus infection model based on human hepatoma line HepG2 stably transfected with the NTCP gene [42]. This model, which maintains a full virus replication cycle, was developed in our laboratories for identification of viral entry inhibitors, promising candidates to prevent development of resistant HBV forms [43]. The title molecule 3 demonstrated 86% inhibition of HBV replication (in 10 µM concentration) in this model.…”