Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents against Dengue and Zika Virus Infections

Abstract

Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain–Barré syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzene­sulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

“…In the past decade, there has been a significant effort to develop small molecules for the treatment of DENV infection, yielding multiple promising candidates with a number of different scaffolds. [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] However, none of these compounds have entered clinical trials for DENV treatment. Interestingly, many of these compounds include common kinase inhibitor scaffolds, such as the oxindole [ 14 ], iso thiazolo[4,3- b ]pyridine [ 15 ] and azaindoles [ 16 ].…”

Selective estrogen receptor modulator, tamoxifen, inhibits Zika virus infection

“…Calmodulin-dependent protein kinase II has been implicated as a key factor in the life cycle of the JEV, another member of Flaviviridae, making it an interesting target for further study. 40 A virucidal assay was performed to determine whether TAM and TAM-OH achieve their activity by directly inhibiting ZIKV or whether they elicit a cellular response that inhibits replication. TAM and TAM-OH were pre-incubated with ZIKV, the mixture was diluted 100-fold to produce a small concentration of the compound (500 nM for the highest concentration) and 600 pfu/ml of the virus, and an FFA was used to quantify virucidal activity.…”

“…Calmodulin or calmodulin‐dependent kinases could play key roles in the replication of the virus. Calmodulin‐dependent protein kinase II has been implicated as a key factor in the life cycle of the JEV, another member of Flaviviridae, making it an interesting target for further study 40 …”

Role of Melatonin on Virus-Induced Neuropathogenesis—A Concomitant Therapeutic Strategy to Understand SARS-CoV-2 Infection

“…Moreover, melatonin also suppresses the activation of calcium/calmodulin-dependent kinase II (CaMKII) in axons and promotes nerve regeneration [136]. It is interesting to note that the host CaMKII inhibition is a potential target to develop prophylactic antiviral drugs against Dengue (DENV) and Zika virus (ZIKV) infections [137]. Melatonin exerts anti-inflammatory effects, mainly by inhibiting inflammasome activation and the caspase cascade [138].…”