First Discovery of Novel Cytosine Derivatives Containing a Sulfonamide Moiety as Potential Antiviral Agents.

A series of cytosine derivatives containing a sulfonamide moiety were designed and synthesized, and their antiviral activities against pepper mild mottle virus (PMMoV) were systematically evaluated. Then, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to study the structure-activity relationship according to the pEC50 of the compounds' protective activities. Next, compound A32 with preferable antiviral activity on PMMoV was obtained based on the CoMSIA and CoMFA models, with an EC50 of 19.5 µg/mL, which was superior to the template molecule A25 (21.3 µg/mL) and ningnanmycin (214.0 µg/mL). In addition, further studies showed that the antiviral activity of compound A32 against PMMoV was in accord with the up-regulation of proteins expressed in the defense response and carbon fixation in photosynthetic organisms. These results indicated that cytosine derivatives containing a sulfonamide moiety could be used as novel potential antiviral agents for further research and development.

Synthesis, Anti-Tomato Spotted Wilt Virus Activities, and Interaction Mechanisms of Novel Dithioacetal Derivatives Containing a 4(3H)-Quinazolinone Pyrimidine Ring.

A series of unreported novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC50 values of 144 µg/mL, which was better than those of ningnanmycin (149 µg/mL) and the lead compound xiangcaoliusuobingmi (525 µg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 µM, which was better than those of ningnanmycin (6.2 µM) and xiangcaoliusuobingmi (59.1 µM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents.

Design, Synthesis, and Anti-ToCV Activity of Novel 4(3H)-Quinazolinone Derivatives Bearing Dithioacetal Moiety.

Tomato chlorosis virus (ToCV) has caused great harm to the production of tomato worldwide. To develop efficient anti-ToCV agents, some novel 4(3H)-quinazolinone derivatives containing dithioacetal were designed and synthesized, and their anti-ToCV activities were evaluated by microscale thermophoresis (MST) using ToCV coat protein (ToCV-CP) as a new target. The results showed that some compounds had a strong binding capacity to ToCV-CP. In particular, compounds C5 and C22 have an excellent binding capacity to ToCV-CP, with binding constant values of 0.24 and 0.25 µM, respectively. Additionally, reduced ToCV-CP gene expression levels of 81.05 and 87.59% could be achieved when tomato was treated with compounds C5 and C22, respectively, which were obviously higher than the levels after ningnanmycin (NNM) treatment (43.88%) and lead compound Xiangcaoliusuobingmi (XCLSBM) treatment (63.56%). Therefore, this work indicates that 4(3H)-quinazolinone derivatives containing dithioacetal moiety can be used as novel anti-ToCV agents.

Tomato Chlorosis Virus Minor Coat Protein as a Novel Target To Screen Antiviral Drugs.

Minor coat protein (mCP), an important component of tomato chlorosis virus (ToCV), plays a significant role in the process of virus assembly and movement and is directly related to the virus-insect transmission. Therefore, ToCV mCP could be considered as a potent target for anti-ToCV drugs. In this study, ToCV mCP was first cloned, expressed, purified, and a novel target to screen the antiviral agents. The results showed that some antiviral compounds bound to ToCV mCP with strongly affinities in vitro, including quinazoline derivatives 4a and 4b, Ningnanmycin, and Ribavirin. Subsequently, three-dimensional-quantitative structure-activity relationship (3D-QSAR) analysis was performed based on the binding affinities, and the model indicated that 4a and 4b had indeed stronger binding effects on ToCV mCP than other quinazoline derivatives. Finally, the anti-ToCV activities of compounds 4a and 4b were evaluated by quantitative real-time polymerase chain reaction in vivo. Compounds 4a and 4b inhibited infection of ToCV in the host and as well as reduced the level of ToCV mCP gene expression. Thus, ToCV mCP can be used as a novel drug target for screening anti-ToCV agents, and the ligand-based 3D-QSAR analysis of quinazoline derivatives provided new insights into the design and optimization of novel anti-ToCV drug molecules based on ToCV mCP.

The spectrogram data of quinazoline derivatives containing a dithioacetal moiety.

The nuclear magnetic resonance, and high-resolution mass spectrometry of quinazoline derivatives containing a dithioacetal moiety, which was hosted in the research article entitled "Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety". The data include 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. In this article, a more comprehensive data interpretation and analysis is explained.

Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety.

A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 µg/mL) and curative activity against potato virus Y (EC50 = 350.5 µg/mL), which were better than those of ningnanmycin (357.7 µg/mL and 493.7 µg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.