Evaluating the secondary bioactive metabolites in Geodia corticostylifera / Avaliação dos metabólitos bioativos secundários em Geodia corticostylifera

Ophiactis savignyi could be discovered all over the world in tropical marine environments. People could have aided in the spread of O. savignyi, particularly in the western and eastern populations of Panama's Isthmus. The brittle star Ophiactis savignyi, often known as savigny's brittle star, coexists alongside the sponge Geodia corticostylifera. The focus of this research has been to assess the functional relevance of G. corticostylifera secondary metabolites as antifoulant against mussels, protection against generalist fish, and chemical cues to affiliated brittle stars. Both in flow-through and static seawater laboratory studies, O. savignyi which has previously been connected with sponges, was given both treated and control mimics at the same time. The sponge extract was also tested for its ability to protect fish against predators and fouling. Deterrence test using chemicals indicated that the normal level of the sponge extract may also suppress generalist fish predation in the field as well as the mussel Perna perna's normal attachment in clinical contexts. According to the findings, G. corticostylifera crude extract has many roles in the aquatic environments, apparently being accountable for this sponge's tighter relationship with O. savignyi, which protects the ophiuroid and inhibits epibionts on itself.

Ophiactis savignyi pode ser descoberta em todo o mundo em ambientes marinhos tropicais. A população pode ter contribuído para a propagação de O. savignyi, particularmente as populações ocidentais e orientais do istmo do Panamá. A estrela-quebradiça O. savignyi, muitas vezes conhecida como estrela-quebradiça de Savignyi, coexiste com a esponja Geodia corticostylifera. O foco desta pesquisa foi avaliar a relevância funcional dos metabólitos secundários de G. corticostylifera como anti-incrustante contra mexilhões, proteção contra peixes generalistas e sinais químicos para estrelas-quebradiças afiliadas. Em estudos de laboratório com fluxo contínuo e estático de água do mar, O. savignyi, que anteriormente havia se ligado a esponjas, recebeu mimetizadores tratados e controle ao mesmo tempo. O extrato de esponja também foi testado por sua capacidade de proteger os peixes contra predadores e incrustações. Testes de dissuasão usando produtos químicos indicaram que o nível normal de extrato de esponja também pode suprimir a predação de peixes generalistas no campo, bem como a fixação normal do mexilhão Perna perna em ambientes clínicos. De acordo com os achados, o extrato bruto de G. corticostylifera tem diversas funções em ambientes aquáticos, aparentemente responsáveis ​​pela relação mais próxima dessa esponja com O. savignyi, protegendo o ofiuroide e inibindo os epibiontes.

3D Printed Scaffolds Manufactured with Biosilica from Marine Sponges for Bone Healing in a Cranial Defect in Rats.

The inorganic part of marine sponges, called Biosilica (BS), presents an osteogenic potential and the ability of consolidating fractures. Moreover, 3D printing technique is highly effective for manufacturing scaffolds for tissue engineering proposals. Thus, the aims of this study were to characterize the 3D rinted scaffolds, to evaluate the biological effects in vitro and to investigate the in vivo response using an experimental model of cranial defects in rats. The physicochemical characteristics of 3D printed BS scaffolds were analyzed by FTIR, EDS, calcium assay, evaluation of mass loss and pH measurement. For in vitro analysis, the MC3T3-E1 and L929 cells viability was evaluated. For the in vivo evaluation, histopathology, morphometrical and immunohistochemistry analyses were performed in a cranial defect in rats. After the incubation, the 3D printed BS scaffolds presented lower values in pH and mass loss over time. Furthermore, the calcium assay showed an increased Ca uptake. The FTIR analysis indicated the characteristic peaks for materials with silica and the EDS analysis demonstrated the main presence of silica. Moreover, 3D printed BS demonstrated an increase in MC3T3-E1 and L929 cell viability in all periods analyzed. In addition, the histological analysis demonstrated no inflammation in days 15 and 45 post-surgery, and regions of newly formed bone were also observed. The immunohistochemistry analysis demonstrated increased Runx-2 and OPG immunostaining. Those findings support that 3D printed BS scaffolds may improve the process of bone repair in a critical bone defect as a result of stimulation of the newly formed bone.

Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells.

Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. The role of ER stress in manoalide-induced preferential antiproliferation and apoptosis was assessed in this study. Manoalide induces a higher ER expansion and aggresome accumulation of oral cancer than normal cells. Generally, manoalide differentially influences higher mRNA and protein expressions of ER-stress-associated genes (PERK, IRE1α, ATF6, and BIP) in oral cancer cells than in normal cells. Subsequently, the contribution of ER stress on manoalide-treated oral cancer cells was further examined. ER stress inducer, thapsigargin, enhances the manoalide-induced antiproliferation, caspase 3/7 activation, and autophagy of oral cancer cells rather than normal cells. Moreover, N-acetylcysteine, an ROS inhibitor, reverses the responses of ER stress, aggresome formation, and the antiproliferation of oral cancer cells. Consequently, the preferential ER stress of manoalide-treated oral cancer cells is crucial for its antiproliferative effect.

Molecular Networking Revealed Unique UV-Absorbing Phospholipids: Favilipids from the Marine Sponge Clathria faviformis.

Analysis of extracts of the marine sponge Clathria faviformis by high-resolution LC-MS2 and molecular networking resulted in the discovery of a new family of potentially UV-protecting phospholipids, the favilipids. One of them, favilipid A (1), was isolated and its structure determined by mass and tandem mass spectrometry, NMR, electronic circular dichroism (ECD), and computational studies. Favilipid A, which has no close analogues among natural products, possesses an unprecedented structure characterized by a 4-aminodihydropiridinium core, resulting in UV-absorbing properties that are very unusual for a phospholipid. Consequently, favilipid A could inspire the development of a new class of molecules to be used as sunscreen ingredients. In addition, favilipid A inhibited by 58-48% three kinases (JAK3, IKKß, and SYK) involved in the regulation of the immune system, suggesting a potential use for treatment of autoimmune diseases, hematologic cancers, and other inflammatory states.

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms.

Parasitic diseases still threaten human health. At present, a number of parasites have developed drug resistance, and it is urgent to find new and effective antiparasitic drugs. As a rich source of biological compounds, marine natural products have been increasingly screened as candidates for developing new antiparasitic drugs. The literature related to the study of the antigenic animal activity of marine natural compounds from invertebrates and microorganisms was selected to summarize the research progress of marine compounds and the structure-activity relationship of these compounds in the past five years and to explore the possible sources of potential antiparasitic drugs for parasite treatment.

Dimeric pyrrole-imidazole alkaloids: sources, structures, bioactivities and biosynthesis.

Pyrrole-imidazole alkaloids (PIAs) constitute a highly diverse and densely functionalized subclass of marine natural products. Among them, the uncommon dimeric PIAs with ornate molecular architectures, attractive biological properties and interesting biosynthetic origin have spurred a considerable interest of chemists and biologists. The present review comprehensively summarized 84 dimeric PIAs discovered during the period from 1981 to September 2022, covering their source organisms, chemical structures, biological activities as well as biosynthesis. For a better understanding, these structurally intricate PIA dimers are firstly classified and presented according to their carbon skeleton features as well as biosynthesis pathways. Furthermore, relevant summaries focusing on the source organisms and the associated bioactivities of these compounds belonging to different chemical classes are also provided, which will help elucidate the fascinating chemistry and biology of these unusual PIA dimers.

Potential Utilization of Bacterial Consortium of Symbionts Marine Sponges in Removing Polyaromatic Hydrocarbons and Heavy Metals, Review.

Toxic materials in waste generally contain several components of the global trending pollutant category, especially PAHs and heavy metals. Bioremediation technology for waste management that utilizes microorganisms (bacteria) has not been fully capable of breaking down these toxic materials into simple and environmentally friendly chemical products. This review paper examines the potential application of a consortium of marine sponge symbionts with high performance and efficiency in removing PAHs and heavy metal contaminants. The method was carried out through a review of several related research articles by the author and published by other researchers. The results of the study conclude that the development of global trending pollutant (GTP) bioremediation technology could be carried out to increase the efficiency of remediation. Several types of marine sponge symbiont bacteria, hydrocarbonoclastic (R-1), metalloclastic (R-2), and metallo-hydro-carbonoclastic (R-3), have the potential to be applied to improve waste removal performance. A consortium of crystalline bacterial preparations is required to mobilize into GTP-exposed sites rapidly. Bacterial symbionts of marine sponges can be traced mainly to sea sponges, whose body surface is covered with mucus.

A concise review on marine bromopyrrole alkaloids as anticancer agents.

Natural products have been the most important sources of chemically diverse raw materials that have inspired pharmaceutical discoveries over the past few decades. Many pharmaceutical companies are utilizing plant extracts to develop relatively crude therapeutic formulations. The interesting chemicals identified as natural products are derived from the phenomenon of biodiversity, where the interactions between the organisms and their environment formulate the diverse and complex chemical entities within them that enhance their survival and competitiveness. Marine sponges are rich sources of natural products and have provided an infinite supply of bioactive metabolites. Bromopyrrole alkaloids are a good example of marine metabolites, have a broad range of biological activity, and represent a fascinating example of chemical diversity of secondary metabolites elaborated by marine invertebrates. The isolation and synthesis of this structural class have been investigated, resulting in a series of bromopyrrole alkaloids with potential lead hits. This review presents the detailed isolation and anticancer activity of marine bromopyrrole alkaloids, and will be of interest to the wider research community both in academic and industrial settings.

Effect of extracts from several sponges of Yucatan Coast on Giardia lamblia and preliminary chemical investigation of the bioactive extract of Haliclona (Reinera) tubifera.

In this study, twenty-four organic extracts from six marine sponge species, collected at shallows of Yucatan, Mexico, were evaluated against Giardia lamblia trophozoites and Vero cells. The dichloromethane and hexane extracts of Haliclona tubifera exhibited the highest antigiardiasic activity (IC50 = 1.00 and 2.11 µg/mL, respectively), as well as high selectivity (SI = 41.8 and > 47.4, respectively), while ethyl acetate and methanol extracts of Cinachyrella alloclada, and methanol extract of Suberites aurantiaca showed moderate activity. Contrastingly, the extracts of Halichondria magniculosa and Oceanapia nodosa were considered non actives. Consequently, the dichloromethane extract of H. tubifera were subject to an exploratory chemical study, isolating cholesterol, two benzaldehyde derivatives, three benzoic acid derivatives, cytosine, and thymine.

Marine Sponge Aaptos suberitoides Extract Improves Antiproliferation and Apoptosis of Breast Cancer Cells without Cytotoxicity to Normal Cells In Vitro.

The anticancer effects and mechanisms of marine sponge Aaptos suberitoides were rarely assessed, especially for methanol extract of A. suberitoides (MEAS) to breast cancer cells. This study evaluated the differential suppression effects of proliferation by MEAS between breast cancer and normal cells. MEAS demonstrated more antiproliferation impact on breast cancer cells than normal cells, indicating oxidative stress-dependent preferential antiproliferation effects on breast cancer cells but not for normal cells. Several oxidative stress-associated responses were highly induced by MEAS in breast cancer cells but not normal cells, including the generations of cellular and mitochondrial oxidative stress as well as the depletion of mitochondrial membrane potential. MEAS downregulated cellular antioxidants such as glutathione, partly contributing to the upregulation of oxidative stress in breast cancer cells. This preferential oxidative stress generation is accompanied by more DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in breast cancer cells than in normal cells. N-acetylcysteine reverted these MEAS-triggered responses. In conclusion, MEAS is a potential natural product for treating breast cancer cells with the characteristics of preferential antiproliferation function without cytotoxicity to normal cells in vitro.

Screening and Molecular Docking of Bioactive Metabolites of the Red Sea Sponge Callyspongia siphonella as Potential Antimicrobial Agents.

Marine sponges create a wide range of bioactive secondary metabolites, as documented throughout the year. Several bioactive secondary metabolites were isolated from different members of Callyspongia siphonella species. This study aimed for isolation and structural elucidation of major metabolites in order to investigate their diverse bioactivities such as antimicrobial and anti-biofilm activities. Afterwards, a molecular docking study was conducted, searching for the possible mechanistic pathway of the most bioactive metabolites. Extraction, fractionation, and metabolomics analysis of different fractions was performed in order to obtain complete chemical profile. Moreover, in vitro assessment of different bioactivities was performed, using recent techniques. Additionally, purification, structural elucidation of high features using recent chromatographic and spectroscopic techniques was established. Finally, AutoDock Vina software was used for the Pharmacophore-based docking-based analysis. As a result, DCM (dichloromethane) fraction exerted the best antibacterial activity using disc diffusion method; particularly against S. aureus with an inhibition zone of 6.6 mm. Compound 11 displayed a considerable activity against both MRSA (Methicillin-resistant Staphyllococcus aureus) and Staphyllococcus aureus with inhibition ratios of 50.37 and 60.90%, respectively. Concerning anti-biofilm activity, compounds 1 and 2 displayed powerful activity with inhibition ratios ranging from 39.37% to 70.98%. Pharmacophore-based docking-based analysis suggested elongation factor G (EF-G) to be a probable target for compound 11 (siphonellinol C) that showed the best in vitro antibacterial activity, offering unexplored potential for new drugs and treatment candidates.

Electrolysis as a Universal Approach for Isolation of Diverse Chitin Scaffolds from Selected Marine Demosponges.

Three-dimensional chitinous scaffolds often used in regenerative medicine, tissue engineering, biomimetics and technology are mostly isolated from marine organisms, such as marine sponges (Porifera). In this work, we report the results of the electrochemical isolation of the ready to use chitinous matrices from three species of verongiid demosponges (Aplysina archeri, Ianthella basta and Suberea clavata) as a perfect example of possible morphological and chemical dimorphism in the case of the marine chitin sources. The electrolysis of concentrated Na2SO4 aqueous solution showed its superiority over the chemical chitin isolation method in terms of the treatment time reduction: only 5.5 h for A. archeri, 16.5 h for I. basta and 20 h for the S. clavata sample. Further investigation of the isolated scaffolds by digital microscopy and SEM showed that the electrolysis-supported isolation process obtains chitinous scaffolds with well-preserved spatial structure and it can be competitive to other alternative chitin isolation techniques that use external accelerating factors such as microwave irradiation or atmospheric plasma. Moreover, the infrared spectroscopy (ATR-FTIR) proved that with the applied electrochemical conditions, the transformation into chitosan does not take place.

Rheology of marine sponges reveals anisotropic mechanics and tuned dynamics.

Sponges are animals that inhabit many aquatic environments while filtering small particles and ejecting metabolic wastes. They are composed of cells in a bulk extracellular matrix, often with an embedded scaffolding of stiff, siliceous spicules. We hypothesize that the mechanical response of this heterogeneous tissue to hydrodynamic flow influences cell proliferation in a manner that generates the body of a sponge. Towards a more complete picture of the emergence of sponge morphology, we dissected a set of species and subjected discs of living tissue to physiological shear and uniaxial deformations on a rheometer. Various species exhibited rheological properties such as anisotropic elasticity, shear softening and compression stiffening, negative normal stress, and non-monotonic dissipation as a function of both shear strain and frequency. Erect sponges possessed aligned, spicule-reinforced fibres which endowed three times greater stiffness axially compared with orthogonally. By contrast, tissue taken from shorter sponges was more isotropic but time-dependent, suggesting higher flow sensitivity in these compared with erect forms. We explore ecological and physiological implications of our results and speculate about flow-induced mechanical signalling in sponge cells.

Fused Tricyclic Guanidine Alkaloids: Insights into Their Structure, Synthesis and Bioactivity.

A marine natural product possesses a diverse and unique scaffold that contributes to a vast array of bioactivities. Tricyclic guanidine alkaloids are a type of scaffold found only in marine natural products. These rare skeletons exhibit a wide range of biological applications, but their synthetic approaches are still limited. Various stereochemical assignments of the compounds remain unresolved. Batzelladine and ptilocaulins are an area of high interest in research on tricyclic guanidine alkaloids. In addition, mirabilins and netamines are among the other tricyclic guanidine alkaloids that contain the ptilocaulin skeleton. Due to the different structural configurations of batzelladine and ptilocaulin, these two main skeletons are afforded attention in many reports. These two main skeletons exhibit different kinds of compounds by varying their ester chain and sidechain. The synthetic approaches to tricyclic guanidine alkaloids, especially the batzelladine and ptilocaulin skeletons, are discussed. Moreover, this review compiles the first and latest research on the synthesis of these compounds and their bioactivities, dating from the 1980s to 2022.

Genus Smenospongia: Untapped Treasure of Biometabolites-Biosynthesis, Synthesis, and Bioactivities.

Marine sponges continue to attract remarkable attention as one of the richest pools of bioactive metabolites in the marine environment. The genus Smenospongia (order Dictyoceratida, family Thorectidae) sponges can produce diverse classes of metabolites with unique and unusual chemical skeletons, including terpenoids (sesqui-, di-, and sesterterpenoids), indole alkaloids, aplysinopsins, bisspiroimidazolidinones, chromenes, γ-pyrones, phenyl alkenes, naphthoquinones, and polyketides that possessed diversified bioactivities. This review provided an overview of the reported metabolites from Smenospongia sponges, including their biosynthesis, synthesis, and bioactivities in the period from 1980 to June 2022. The structural characteristics and diverse bioactivities of these metabolites could attract a great deal of attention from natural-product chemists and pharmaceuticals seeking to develop these metabolites into medicine for the treatment and prevention of certain health concerns.

Antimicrobial and cytotoxic effects of marine sponge extracts Agelas clathrodes, Desmapsamma anchorata and Verongula rigida from a Caribbean Island.

Although marine sponges are known for their antimicrobial, antifungal and cytotoxic activity, very few studies have been carried out on endemic species of Martinique. Martinique is part of the Agoa Sanctuary, a marine protected area that includes the exclusive economic zones (EEZ) of the French Caribbean islands, making it an abundant source of marine species. To highlight the potential of this area for the discovery of marine biomolecules with antipathogenic and antitumor activities, we tested the aqueous and ethanolic extracts of sponge species Agelas clathrodes, Desmapsamma anchorata and Verongula rigida. Five bacterial strains: Bacillus cereus (CIP 78.3), Escherichia coli (CIP 54.127), Pseudomonas aeruginosa (CIP A22), Staphylococcus aureus (CIP 67.8) and Staphylococcus saprophyticus (CIP 76125) were evaluated, as well as four tumor cell lines: breast cancer (MDA-MB231), glioblastoma (RES259) and leukemia (MOLM14 and HL-60). Antimicrobial activity was evaluated using the disc diffusion technique by determining the minimum inhibitory and minimum bactericidal concentrations. Tumor cytotoxic activity was determined in vitro by defining the minimum concentration of extracts that would inhibit cell growth. Ethanolic extracts of Agelas clathrodes were bactericidal for Staphylococcus aureus and Staphylococcus saprophyticus strains, as well as strongly cytotoxic (IC50 < 20 µg/mL) on all cancer cell lines. Verongula rigida also showed strong cytotoxic activity on cell lines but no antimicrobial activity. These results are innovative for this species on these bacterial lines, highlighting the potential of sponge extracts from this area as bioactive compounds sources.

Marine Sponges in a Snowstorm - Extreme Sensitivity of a Sponge Holobiont to Marine Oil Snow and Chemically Dispersed Oil Pollution.

Holobionts formed by a host organism and associated symbionts are key biological units in marine ecosystems where they are responsible for fundamental ecosystem services. Therefore, understanding anthropogenic impacts on holobionts is essential. Sponges (Phylum Porifera) are ideal holobiont models. They host a complex microbial community and provide ecosystem services including nutrient cycling. At bathyal depths, sponges can accumulate forming dense sponge ground habitats supporting biodiverse associated communities. However, the impacts of spilled oil and dispersants on sponge grounds cannot be understood without considering exposures mediated through sponge filtration of marine snow particles. To examine this, we exposed the model sponge Halichondria panicea to oil, dispersant and "marine oil snow" contaminated seawater and elucidate the complex molecular response of the holobiont through metatranscriptomics. While the host response included detoxification and immune response pathways, the bacterial symbiotic response differed and was at least partially the result of a change in the host environment rather than a direct response to hydrocarbon exposure. As the sponge host reduced its pumping activity and internal tissue oxygen levels declined, the symbionts changed their metabolism from aerobic to anaerobic pathways possibly via quorum sensing. Furthermore, we found evidence of hydrocarbon degradation by sponge symbionts, but sponge mortality (even when exposed to low concentrations of hydrocarbons) implied this may not provide the holobiont with sufficient resilience against contaminants. Given the continued proposed expansion of hydrocarbon production into deep continental shelf and slope settings where sponge grounds form significant habitats it is important that dispersant use is minimised and that environmental impact assessments carefully consider the vulnerability of sponge holobionts.

Fluxes of the Amazon River plume nutrients and microbes into marine sponges.

Sponges have co-evolved with microbes for over 400 myr. Previous studies have demonstrated that sponges can be classified according to the abundance of microbes in their tissues as Low Microbial Abundance (LMA) and High Microbial Abundance (HMA). While LMA sponges rely mainly on water column microbes, HMA appear to rely much more on symbiotic fermentative and autotrophic microbes maintained in their tissues. However, it is unclear if this pattern holds when comparing different species of tropical sponges under extreme nutrient conditions and sediment loads in the water column, such as the Great Amazon Reef System (GARS), which covers an area of ~56,000 km2 off the Amazon River mouth. Sponges are the major GARS benthic components. However, these sponges' microbiome across the GARS is still unknown. Here, we investigated water quality, isotopic values (δ13C and δ15N), metagenomic and lipidomic profiles of sponges obtained from different sectors throughout the GARS. >180 million shotgun metagenomic reads were annotated, covering 22 sponge species. Isotopic and lipidomic analyses suggested LMA sponges rely on the Amazon River Plume for nutrition. HMA sponges (N = 15) had higher Roseiflexus and Nitrospira abundance, whereas LMA sponges (N = 7) had higher Prochlorococcus and Pelagibacter abundance. Functional data revealed that the LMA sponge microbiomes had greater number of sequences related to phages and prophages as well as electron transport and photophosphorylation which may be related to photosynthetic processes associated with the Prochlorococcus and Synechococcus found in the LMA. The higher phages abundance in LMA sponges could be related to these holobionts' reduced defense towards phage infection. Meanwhile, HMA sponge microbiomes had higher Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR abundance, which may be involved in defense against phage infection. This study sheds light on the nutrient fluxes and microbes from the Amazon River plume into the sponge holobionts.

Application of SS-CS-HR-AAS measurements for the detection of Ag nanoparticles in marine invertebrates.

The present study describes the development of a fit-for-purpose analytical procedure for the detection of Ag NPs in different marine organisms by Solid Sampling Continuous Source High Resolution Atomic Absorption Spectrometry (SS-CS-HR-AAS). The detection is based on the observation of the Ag absorption peak and its atomization delay tad which is different for ionic Ag and Ag NPs. The temperature program was optimized in order to achieve the maximum difference between the t ad (Δtad ). The method was first developed using biota CRMs spiked with different Ag NPs standard solutions or Ag+ , at the same concentration. Then, laboratory exposure experiments were performed on mussels and marine sponges. The results showed that the developed methodology is suitable for the detection of Ag NPs for both groups of organisms, showing Δtad up to 3.1 s. The developed method is therefore a promising tool to assess the presence of AgNPs in marine invertebrates.

Investigating the structure-activity relationship of marine polycyclic batzelladine alkaloids as promising inhibitors for SARS-CoV-2 main protease (Mpro).

Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (Mpro) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (Mpro) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H-I (8-9) and batzelladines F-G (6-7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (Mpro) pocket residues. The best two chemical hits, batzelladines H-I (8-9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (Mpro) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N-OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals.