Hery Suwito

To identify and develop effective antiviral agents against SARS-CoV-2, research is ongoing in the field of drug discovery. Heterocyclic compounds such as Chalcone, Chromene, and Dihydropyrimidinone (DHPM) derivatives are of particular interest because of their structural diversity, easily synthesized and broad pharmacological activities, including antiviral effects. Therefore, we investigated the potential of these derivatives against SARS-CoV-2 using cell-based assays, supported by in silico studies. Ten synthetic compounds, consist of 4 DHPMs, 2 chromenes, and 4 chalcones were tested for cytotoxicity and antiviral activity in Vero cells infected with a locally isolated SARS-CoV-2 strain (Clade GH, GISAID: EPI_ISL_529965), using a phenotypic screening approach. Moreover, in silico analyses were performed to predict their drug-likeness, including absorption, distribution, metabolism, and excretion properties, using SwissADME. Molecular docking was conducted to evaluate the binding affinity and interactions of compounds with the SARS-CoV-2 main protease (Mpro). Among the tested compounds, S-10 (chromene derivative) and S-12 (DHPM derivative) demonstrated exhibited significant antiviral activity compared to the other tested derivatives (p < 0.05), with IC₅₀ values of 8.52 ± 0.28 µM and 6.19 ± 0.41 µM, and selectivity index (SI) of 158.8 and 309.7, respectively, indicating strong efficacy and high safety margins. In silico ADME suggested favorable drug-likeness profiles without major toxicity alerts. Molecular docking further revealed that both compounds established stable interactions with the SARS-CoV-2 main protease (Mpro), particularly at the catalytic residues His-41 and Cys-145, supporting their in vitro activity. These results suggest their potential as lead compounds for further drug development, supporting the use of integrated phenotypic and computational approaches in the discovery of region-specific antiviral agents. HIGHLIGHTS Two novel compounds (S-10 and S-12) were identified with strong anti-SARS-CoV-2 activity and high selectivity index (SI > 100), compared to the other 8 compounds tested, out of 10 Dihydropyrimidinone, Chromene, and Chalcone derivative candidates, suggesting high efficacy and low cytotoxicity. Phenotypic screening was performed against a locally isolated SARS-CoV-2 strain (Clade GH, Indonesia) provided, direct biological relevance rather than relying solely on predictive models and supporting region-specific therapeutic development. Supplementary in silico analysis (ADME profiling, toxicity prediction, and molecular docking to Mpro) offers, a comprehensive assessment of efficacy, safety, and mechanism of action. GRAPHICAL ABSTRACT

Etlingera balikpapanensis, a rhizomatous plant native to East Kalimantan and a member of the Zingiberaceae family, shows great promise for use in traditional medicine. This research investigated the biological activities of the essential oils derived from the rhizome of E. balikpapanensis for their antidiabetic and antioxidant activities, and molecular docking analysis of their chemical constituents for the first time. The essential oils were extracted via hydrodistillation, and their chemical composition was analyzed using gas chromatography/mass spectrometry (GC/MS). The essential oils were evaluated for their antidiabetic properties through the inhibition of α-glucosidase, using molecular docking techniques. The evaluation aimed to investigate the inhibitory effects of essential oil compounds on the target protein with their potential antidiabetic properties. A total of 62 volatile compounds were identified, with eucalyptol (3.06%), linalool (8.74%), benzyl benzoate (15.24%), and 2-propenoic acid, 3-phenyl, phenylmethyl ester, (E) (14.63%) identified as the predominant constituents. These essential oils demonstrated significant antioxidant activities against ABTS and nitric oxide free radicals compared to ascorbic acid. Furthermore, the α-glucosidase inhibitory activity of the essential oils demonstrated an IC50 value comparable to acarbose as the positive control. In the in silico analysis, the major compounds derived from the essential oils yielded significant insights for molecular docking by the GOLD score assessment. This study indicates that the essential oils extracted from the rhizome of E. balikpapanensis possess potential antidiabetic and antioxidant properties, thereby underscoring their potential as a functional secondary agentthat may mitigate the risks associated with diabetic complications.

The novel coronavirus SARS-CoV-2, responsible for the global COVID-19 pandemic, was first identified in Wuhan, China, in December 2019. Despite extensive research, an effective treatment remains elusive, with most existing therapies involving repurposed drugs. Key targets for antiviral drug development include the viral protease enzymes Main Protease (Mpro) and Papain-Like Protease (PLPro), both critical for viral replication and immune evasion. Mpro contains a catalytic dyad (His41, Cys145), while PLPro features a catalytic triad (Cys111, His273, Asp287), both essential for the virus's lifecycle. Chromene and Dihydropyrimidinone (DHPM) compounds, known for their diverse biological activities, have not been fully explored as potential treatments for SARS-CoV-2. Previous research as preliminary study identified four compounds that passed cytotoxicity tests and antiviral bioassays against SARS-CoV-2, with IC50 values ranging from 6.187µM to 25.21µM. Based on these findings, the current research aims to design new derivatives of DHPM and chromene compounds by introducing 14 functional groups to the aromatic rings of these lead compounds. As a result, a database of 838 new derivatives was generated. These derivatives were then analyzed through computational screening and molecular docking studies to evaluate their binding interactions with the viral protease targets. The screening process employed a selection score (SS) system based on ADMET properties and docking scores, allowing for the identification of the most promising candidates in comparison to reference drugs. Three compounds were identified with higher SS values: (R)-2-amino-4-(2,4-diethoxy-5-methylphenyl)-7-hydroxy-4H-chromene-3-carbonitrile, (R)-2-amino-4-(2,4-diethoxy-5-fluorophenyl)-7-hydroxy-4H-chromene-3-carbonitrile, and (R)-2-amino-4-(5-(dimethylamino)-2,4-diethoxyphenyl)-7-hydroxy-4H-chromene-3-carbonitrile. These compounds are considered promising candidates for further development as potential anti-SARS-CoV-2 drugs due to their favorable pharmacokinetic profiles and docking results.

Apart from natural products and synthesis, phenolic compounds can be produced from the depolymerization of lignin, a major waste in biofuel and paper production. This process yields a plethora of aryl propanoid phenolic derivatives with broad biological activities, especially antioxidant properties. Due to its versatility, our study focuses on investigating the antioxidant mechanisms of several phenolic compounds obtained from renewable and abundant resources, namely, syringol (Hs), 4-allylsyringol (HAs), 4-propenylsyringol (HPns), and 4-propylsyringol (HPs). Employing the density functional theory (DFT) approach in conjunction with the QM-ORSA protocol, we aim to explore the reactivity of these compounds in neutralizing hydroperoxyl radicals in physiological and non-polar media. Kinetic and thermodynamic parameter calculations on the antioxidant activity of these compounds were also included in this study. Additionally, our research utilizes the activation strain model (ASM) for the first time to explain the reactivity of the HT and RAF mechanisms in the peroxyl radical scavenging process. It is predicted that HPs has the best rate constant in both media (1.13 × 10⁸ M⁻¹ s⁻¹ and 1.75 × 10⁸ M⁻¹ s⁻¹, respectively). Through ASM analysis, it is observed that the increase in the interaction energy due to the formation of intermolecular hydrogen bonds during the reaction is an important feature for accelerating the hydrogen transfer process. Furthermore, by examining the physicochemical and toxicity parameters, only Hs is not suitable for further investigation as a therapeutic agent because of potential toxicity and mutagenicity. However, overall, all compounds are considered potent HOO˙ scavengers in lipid-rich environments compared to previously studied antioxidants.

Cyclooxygenase-2 (COX-2) is an enzyme involved in inflammation. The overexpression of COX-2 causes chronic inflammation, which can be prevented by COX-2 inhibitors. Generally, COX-2 inhibitors possess a carboxyl group and an aromatic ring in their molecular structure. These moieties are involved in the interaction with the active site of COX-2, thus playing a pivotal role in the inhibitory activity. Regarding the requisite molecular structure of COX-2 inhibitors, derivatives of dihydropyrimidinone (DHPM) are ideal candidates to be explored as COX-2 inhibitors, due to the ease of synthesis and their versatility to be transformed chemically. In this study, we prepared a novel small library consisting of 288 designed DHPM derivatives by varying the constituent components. The selection criteria of potential candidates for the COX-2 inhibitor of the data bank involve in silico studies via molecular docking investigations, prediction of ADMET and druglikeness, as well as molecular dynamics (MD) simulations. Molecular docking served as the initial step of selection, based on the comparison of grid score, docking pose, and interactions with those of lumiracoxib (LUR) as the original ligand of COX-2. The next criteria of selection were scores obtained from the ADMET and druglikeness by comparing the designed candidates with COX-2 inhibitors that were already marketed. Compound RDUE2 and SDT29 were the most potential candidates, which were further analyzed using the MD simulation. The results of the MD simulation indicated that RDUE2 and SDT29 interacted stably with amino acid residues on the active site of COX-2. The estimation of binding free energy indicated that SDT29 exhibited an inhibitory activity comparable to that of LUR, whereas RDUE2 showed a lower inhibitory activity than that of SDT29 and LUR.

Bergenin is a polyphenolic compound that contains isocoumarin skeletal derived from C -glycosylated 4- O -methylgallic acid. The biological activities of this compound and its derivatives are quite diverse. Recent studies reveal neuroprotective effects in vitro and in vivo in Alzheimer's. Norbergenin is a demethylated form of bergenin, known for better antioxidant capacity and associated with neuroprotective properties through oxidative stress inhibition. This study focused on investigating the scavenging mechanism of norbergenin with the ^• OH, ^• OOH, and O 2 ∙ − as a radical model under physiological and lipid environments. The thermodynamic and kinetic parameters of the hydrogen transfer (HT), single electron transfer (SET), sequential proton lost-electron transfer (SPLET) and radical adduct formation (RAF) mechanisms were determined theoretically by the density functional theory (DFT) at M06-2X/6-311 + + G(d,p) level of theory. Based on the computational results, this compound has proved as an excellent ^• OOH and ^• OH scavenger under physiological conditions better than Trolox and vitamin C, whereas its radical demonstrated as an efficient O 2 ∙ − scavenger.

Dihydropyrimidine derivatives possess great potential to be used as a precursor for the synthesis of wide diverse dihydropyrimidine-like derivatives. In this research, the title compounds were synthesized through the reaction between 5-acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione and 2,5-dimethoxybenzladehyde under aldol condensation condition. The title compound, (E)-3-(2,5-dimethoxyphenyl)-1-{[(4-(2,5-dimethoxyphenyl)-6-((E)-2,5-dimethoxystyryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)]}prop-2-en-1-one (yield 15%), was obtained as major product, whereas (E)-3-(2,5-dimethoxyphenyl)-1-{[(4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro pyrimidin-5-yl)]}prop-2-en-1-one (yield 8%) as side product through vinylogous aldol condensation.

Background. One of methoxy aminochalcone derivatives, (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one has been synthesized and proven it's in vitro antiplasmodial activity. In this study, we reported in vivo antiplasmodial activity of this compound against Plasmodium berghei infected mice. Its effect on the haemozoin and erythrocytes stomatocytes formations was also evaluated. Methods. The in vivo antiplasmodial activity was evaluated on P. berghei infected mice by the classical 4-day suppressive test. The effect of the tested compound on the haemozoin formation inhibition was evaluated by flowcytometry, whereas its effect on the stomatocytes formation was evaluated by microscopic examination of the thin blood smear. Doxucycline was used as positive control. The median effective dose (ED₅₀), which is the dose leading to 50% parasite growth inhibition or haemozoin formation inhibition or stomatocytes formation of tested compound and doxycycline were determined using probit analysis and compared using t test. Results: The ED₅₀ of tested compound to parasite growth inhibition were 17.36 ± 4.59 mg/kg BW. Furthermore, this compound exhibited on inhibition of haemozoin formation with the ED₅₀ of 18.56±5.19 mg/kg BW and induction of stomatoytes formation with the ED₅₀ more than > 160 mg/kg BW. Conclusion: The (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)prop-2-en-1-one exhibits potent antimalarial activity via inhibition of haemozoin formation and induction of stomatocytes formation. This compound might be developed into a new antimalarial drug.

A derivative of dihydrotetrazolopyrimidine has been successfully synthesized through a cyclocondensation reaction between a chalcone derivative with 5-aminotetrazole. The molecular structure of the title compound was established based on Fourier transform infrared spectra (FTIR), high-resolution mass spectrometry (HRMS), 1D and 2D nuclear magnetic resonance (NMR) spectrum.

A new compound (E)-3-[3-(4-morpholinophenyl)acryloyl]-2H-chromen-2-one, a coumarin based chalcone derivative, has been successfully synthesized employing a molecular hybridization method through the reaction between 3-acetylcoumarin and 4-morpholinobenzaldehyde using a Claisen–Schmidt reaction using pTSA as a catalyst. The structure of the title compound was established using spectroscopic data FTIR, HRESI-MS, ¹H- and ¹³C-NMR. The anticancer activity against breast cancer cells line T47D and cervix cancer cells line HeLa was determined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.