A Short and Improved Synthesis of the Antiprotozoal Abietane Diterpenoid (-)-Sugikurojin A

Financial support from the Spanish Government [Consejo Superior de Investigaciones Cientificas (201680I008)] is gratefully acknowledgedGonzález-Cardenete, MA.; Zaragoza, RJ. (2017). A Short and Improved Synthesis of the Antiprotozoal Abietane Diterpenoid (-)-Sugikurojin A. Synthesis. 49(6):1315-1318. https://doi.org/10.1055/s-0036-1588353S1315131849

A theoretical study on NHC-catalysed enantioselective cycloaddition of ketenes and 3-aroylcoumarins: mechanism and enantioselectivity

[EN] The NHC-catalysed enantioselective cycloaddition of ketenes to 3-aroylcoumarins to yield dihydrocoumarin-fused dihydropyranones has been investigated using DFT methods at the B3LYP/6-31G* and MPWB1K/6-311G** computational levels. Two plausible mechanisms have been studied: the ¿ketene-first¿ mechanism A and the ¿coumarin-first¿ mechanism B. An analysis of the activation Gibbs free energies involved in the two competitive pathways makes it possible to rule out the pathway associated with the ¿coumarin-first¿ mechanism B. The first step of the ¿ketene-first¿ mechanism A is the formation of zwitterionic intermediate IN1-Z via nucleophilic attack of NHC 1 to ketene 2. [4+2] cycloaddition through nucleophilic attack of enolate IN1-Z to the conjugate double bond of benzoyl group of the coumarin 3, via TS3-SS-a2 or TS3-RR-a2, yield IN3. Finally the extrusion of catalyst through TS5 leads to the final products either 4-SS or 4-RR. Enantioselectivity observed in the experimental results is determined in the transition states TS3-SS-a2/ TS3-RR-a2. In this path, the intramolecular hydrogen-bonding between the hydroxyl group of the IN1-Z adduct and the carbonyl oxygen of the original ketene group directs the final stereochemistry throughout the entire process.This study was supported by intramural grant 201680I008 from the Spanish Government (Consejo Superior de Investigaciones Cientificas).Zaragoza, RJ.; Aurell, MJ.; González-Cardenete, MA. (2018). A theoretical study on NHC-catalysed enantioselective cycloaddition of ketenes and 3-aroylcoumarins: mechanism and enantioselectivity. Organic & Biomolecular Chemistry. 16(30):5474-5482. https://doi.org/10.1039/c8ob01035hS547454821630Flanigan, D. M., Romanov-Michailidis, F., White, N. A., & Rovis, T. (2015). Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chemical Reviews, 115(17), 9307-9387. doi:10.1021/acs.chemrev.5b00060Wang, Y., Wei, D., & Zhang, W. (2017). Recent Advances on Computational Investigations ofN-Heterocyclic Carbene Catalyzed Cycloaddition/Annulation Reactions: Mechanism and Origin of Selectivities. ChemCatChem, 10(2), 338-360. doi:10.1002/cctc.201701119Mahatthananchai, J., & Bode, J. W. (2014). On the Mechanism of N-Heterocyclic Carbene-Catalyzed Reactions Involving Acyl Azoliums. Accounts of Chemical Research, 47(2), 696-707. doi:10.1021/ar400239vBugaut, X., & Glorius, F. (2012). Organocatalytic umpolung: N-heterocyclic carbenes and beyond. Chemical Society Reviews, 41(9), 3511. doi:10.1039/c2cs15333eZhang, Y.-R., Lv, H., Zhou, D., & Ye, S. (2008). ChiralN-Heterocyclic Carbene-Catalyzed Formal [4+2] Cycloaddition of Ketenes with Enones: Highly Enantioselective Synthesis oftrans- andcis-δ-Lactones. Chemistry - A European Journal, 14(28), 8473-8476. doi:10.1002/chem.200801165Huang, X.-L., He, L., Shao, P.-L., & Ye, S. (2008). [4+2] Cycloaddition of Ketenes withN-Benzoyldiazenes Catalyzed by N-Heterocyclic Carbenes. Angewandte Chemie International Edition, 48(1), 192-195. doi:10.1002/anie.200804487Zhang, Y.-R., He, L., Wu, X., Shao, P.-L., & Ye, S. (2008). Chiral N-Heterocyclic Carbene Catalyzed Staudinger Reaction of Ketenes with Imines:  Highly Enantioselective Synthesis ofN-Boc β-Lactams. Organic Letters, 10(2), 277-280. doi:10.1021/ol702759bDuguet, N., Campbell, C. D., Slawin, A. M. Z., & Smith, A. D. (2008). N-Heterocyclic carbene catalysed β-lactam synthesis. Organic & Biomolecular Chemistry, 6(6), 1108. doi:10.1039/b800857bWei, D., Zhu, Y., Zhang, C., Sun, D., Zhang, W., & Tang, M. (2011). A DFT study on enantioselective synthesis of aza-β-lactams via NHC-catalyzed [2+2] cycloaddition of ketenes with diazenedicarboxylates. Journal of Molecular Catalysis A: Chemical, 334(1-2), 108-115. doi:10.1016/j.molcata.2010.11.004Zhang, M., Wei, D., Wang, Y., Li, S., Liu, J., Zhu, Y., & Tang, M. (2014). DFT study on the reaction mechanisms and stereoselectivities of NHC-catalyzed [2 + 2] cycloaddition between arylalkylketenes and electron-deficient benzaldehydes. Organic & Biomolecular Chemistry, 12(33), 6374. doi:10.1039/c4ob00606bWang, X.-N., Shen, L.-T., & Ye, S. (2011). NHC-Catalyzed Enantioselective [2 + 2] and [2 + 2 + 2] Cycloadditions of Ketenes with Isothiocyanates. Organic Letters, 13(24), 6382-6385. doi:10.1021/ol202688hWang, X.-N., Lv, H., Huang, X.-L., & Ye, S. (2009). Asymmetric esterification of ketenes catalyzed by an N-heterocyclic carbene. Org. Biomol. Chem., 7(2), 346-350. doi:10.1039/b815139cWang, X.-N., Shen, L.-T., & Ye, S. (2011). Enantioselective [2+2+2] cycloaddition of ketenes and carbon disulfide catalyzed by N-heterocyclic carbenes. Chemical Communications, 47(29), 8388. doi:10.1039/c1cc12316eDouglas, J., Ling, K. B., Concellón, C., Churchill, G., Slawin, A. M. Z., & Smith, A. D. (2010). NHC-Mediated Chlorination of Unsymmetrical Ketenes: Catalysis and Asymmetry. European Journal of Organic Chemistry, 2010(30), 5863-5869. doi:10.1002/ejoc.201000864Tang, K., Wang, J., Cheng, X., Hou, Q., & Liu, Y. (2010). Theoretical Investigations towards the Staudinger Reaction Catalyzed by N-Heterocyclic Carbene: Mechanism and Stereoselectivity. European Journal of Organic Chemistry, 2010(32), 6249-6255. doi:10.1002/ejoc.201000774Zhang, W., Zhu, Y., Wei, D., Li, Y., & Tang, M. (2012). Theoretical Investigations toward the [4 + 2] Cycloaddition of Ketenes with N-Benzoyldiazenes Catalyzed by N-Heterocyclic Carbenes: Mechanism and Enantioselectivity. The Journal of Organic Chemistry, 77(23), 10729-10737. doi:10.1021/jo302044nRan, Y., Tang, M., Wang, Y., Wang, Y., Zhang, X., Zhu, Y., … Zhang, W. (2016). Theoretical investigations towards the [4+2] cycloaddition of ketenes with 1-azadienes catalyzed by N -heterocyclic carbenes: mechanism and stereoselectivity. Tetrahedron, 72(35), 5295-5300. doi:10.1016/j.tet.2016.06.057Jian, T.-Y., Chen, X.-Y., Sun, L.-H., & Ye, S. (2013). N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition of ketenes and 3-aroylcoumarins: highly enantioselective synthesis of dihydrocoumarin-fused dihydropyranones. Org. Biomol. Chem., 11(1), 158-163. doi:10.1039/c2ob26804cAurell, M. J., Domingo, L. R., Arnó, M., & Zaragozá, R. J. (2016). A DFT study of the mechanism of NHC catalysed annulation reactions involving α,β-unsaturated acyl azoliums and β-naphthol. Organic & Biomolecular Chemistry, 14(35), 8338-8345. doi:10.1039/c6ob01442aDomingo, L. R., Zaragozá, R. J., & Arnó, M. (2011). Understanding the cooperative NHC/LA catalysis for stereoselective annulation reactions with homoenolates. A DFT study. Organic & Biomolecular Chemistry, 9(19), 6616. doi:10.1039/c1ob05609cDomingo, L. R., Zaragozá, R. J., & Arnó, M. (2010). Understanding the mechanism of stereoselective synthesis of cyclopentenes via N-heterocyclic carbene catalyzed reactions of enals with enones. Organic & Biomolecular Chemistry, 8(21), 4884. doi:10.1039/c0ob00088dR. G. Parr and W.Yang , Density Functional Theory of Atoms and Molecules , Oxford University Press , New York , 1989Ziegler, T. (1991). Approximate density functional theory as a practical tool in molecular energetics and dynamics. Chemical Reviews, 91(5), 651-667. doi:10.1021/cr00005a001Becke, A. D. (1993). Density‐functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, 98(7), 5648-5652. doi:10.1063/1.464913Lee, C., Yang, W., & Parr, R. G. (1988). Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B, 37(2), 785-789. doi:10.1103/physrevb.37.785W. J. Hehre , L.Radom , P.von R.Schleyer and J. A.Pople , Ab initio Molecular Orbital Theory , Wiley , New York , 1986Fukui, K. (1970). Formulation of the reaction coordinate. The Journal of Physical Chemistry, 74(23), 4161-4163. doi:10.1021/j100717a029Gonzalez, C., & Schlegel, H. B. (1990). Reaction path following in mass-weighted internal coordinates. The Journal of Physical Chemistry, 94(14), 5523-5527. doi:10.1021/j100377a021Gonzalez, C., & Schlegel, H. B. (1991). Improved algorithms for reaction path following: Higher‐order implicit algorithms. The Journal of Chemical Physics, 95(8), 5853-5860. doi:10.1063/1.461606Zhao, Y., & Truhlar, D. G. (2004). Hybrid Meta Density Functional Theory Methods for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions:  The MPW1B95 and MPWB1K Models and Comparative Assessments for Hydrogen Bonding and van der Waals Interactions. The Journal of Physical Chemistry A, 108(33), 6908-6918. doi:10.1021/jp048147qTomasi, J., & Persico, M. (1994). Molecular Interactions in Solution: An Overview of Methods Based on Continuous Distributions of the Solvent. Chemical Reviews, 94(7), 2027-2094. doi:10.1021/cr00031a013B. Y. Simkin and I.Sheikhet , Quantum Chemical and Statistical Theory of Solutions-A Computational Approach , Ellis Horwood , London , 1995Cancès, E., Mennucci, B., & Tomasi, J. (1997). A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics. The Journal of Chemical Physics, 107(8), 3032-3041. doi:10.1063/1.474659Cossi, M., Barone, V., Cammi, R., & Tomasi, J. (1996). Ab initio study of solvated molecules: a new implementation of the polarizable continuum model. Chemical Physics Letters, 255(4-6), 327-335. doi:10.1016/0009-2614(96)00349-1Barone, V., Cossi, M., & Tomasi, J. (1998). Geometry optimization of molecular structures in solution by the polarizable continuum model. Journal of Computational Chemistry, 19(4), 404-417. doi:10.1002/(sici)1096-987x(199803)19:43.0.co;2-

Synthesis and antileishmanial activity of C7-and C12-functionalized dehydroabietylamine derivatives

Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 mu M), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives. (C) 2016 Elsevier Masson SAS. All rights reserved.Financial support by the Spanish Government MINECO is gratefully acknowledged.Dea-Ayuela, MA.; Bilbao-Ramos, P.; Bolás-Fernández, F.; González-Cardenete, MA. (2016). Synthesis and antileishmanial activity of C7-and C12-functionalized dehydroabietylamine derivatives. European Journal of Medicinal Chemistry. 121:445-450. doi:10.1016/j.ejmech.2016.06.004S44545012

Antifungal Activity of Amphiphilic Perylene Bisimides

[EN] Perylene-based compounds, either naturally occurring or synthetic, have shown interesting biological activities. In this study, we report on the broad-spectrum antifungal properties of two lead amphiphilic perylene bisimides, compounds 4 and 5, which were synthesized from perylene-3,4,9,10-tetracarboxylic dianhydride by condensation with spermine and an ammonium salt formation. The antifungal activity was evaluated using a collection of fungal strains and clinical isolates from patients with onychomycosis or sporotrichosis. Both molecules displayed an interesting antifungal profile with MIC values in the range of 2-25 mu M, being as active as several reference drugs, even more potent in some particular strains. The ammonium trifluoroacetate salt 5 showed the highest activity with a MIC value of 2.1 mu M for all tested Candida spp., two Cryptococcus spp., two Fusarium spp., and one Neoscytalidium spp. strain. Therefore, these amphiphilic molecules with the perylene moiety and cationic ammonium side chains represent important structural features for the development of novel antifungals.This study was supported by grant 201680I008 (awarded to M.A.G.-C.) from the Spanish Government (Consejo Superior de Investigaciones Cientificas) and grant 3756 of the University of Antioquia.Roa-Linares, VC.; Mesa-Arango, AC.; Zaragoza, RJ.; González-Cardenete, MA. (2022). Antifungal Activity of Amphiphilic Perylene Bisimides. Molecules. 27(20):1-12. https://doi.org/10.3390/molecules27206890112272

Anti-Zika virus activity of several abietane-type ferruginol analogues

[EN] Abietane diterpenoids are naturally occurring plant metabolites with a broad spectrum of biological effects including antibacterial. antileishmanial, antitumor, antioxidant, as well as antiinfiammatory activities. Recently, we found that some analogues of natural ferruginol (2) actively inhibited dengue virus 2 (DENV-2) replication. Due to the similarity with DENY, we envisaged that abietane diteipenoids would also be active against Zika virus (ZIKV). Six selected semi-synthetic abietane derivatives of (+)-dehydroabietylatnine (3) were tested. Cytotoxicity was determined by Mn' assay in Vero cells. In vitro anti-ZIKV (clinical isolate. imT17) activity was evaluated by plaque assay. Interestingly, these molecules showed potential as anti-ZIKV agents, with EC50 values ranging from 0.67 to 18.57 mu M. and cytotoxicity (CC50 values) from 256 to 35.09 mu M. The 18-Oxoferruginol (8) (EC50 = 2.60 mu M, SI = 13.51) and 12-nitro-N-benzoyldehydroabietylamine (9) (ECG 0.67 mu M, SI = 3.82) were the most active compounds, followed by 12-hydroxy-N-tosyldehydroabietylamine (7) (EC50 = 3.58 mu M, SI = 3.20) and 12-hydroxy-N,N-phthaloyldehydroabietylamine (5) (EC50 = 7.76 mu M, SI = 1.23). To the best of our knowledge, this is the first report on anti-Zika virus properties of abietanes.Financial support from the Universitat Politecnica de Valencia, under a cooperation "ADSIDEO" research grant (AD1902), is gratefully acknowledged. We are also gratefully to the financial support of the Sao Paulo Research Foundation (FAPESP), grants No 2013/01690-0, No 2019/03859-9, and FAPESP Scholarship No 2013/017029 to FTGS.Sousa, FTG.; Nunes, C.; Malta Romano, C.; Cerdeira Sabino, E.; González-Cardenete, MA. (2020). Anti-Zika virus activity of several abietane-type ferruginol analogues. Revista do Instituto de Medicina Tropical de São Paulo. 62:1-4. https://doi.org/10.1590/S1678-9946202062097S1462Newman, D. J., & Cragg, G. M. (2020). Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. Journal of Natural Products, 83(3), 770-803. doi:10.1021/acs.jnatprod.9b01285Hanson, J. R., Nichols, T., Mukhrish, Y., & Bagley, M. C. (2019). Diterpenoids of terrestrial origin. Natural Product Reports, 36(11), 1499-1512. doi:10.1039/c8np00079dGonzález, M. A. (2015). Aromatic abietane diterpenoids: their biological activity and synthesis. Natural Product Reports, 32(5), 684-704. doi:10.1039/c4np00110aBrandt, C. W., & Neubauer, L. G. (1939). 221. Miro resin. Part I. Ferruginol. Journal of the Chemical Society (Resumed), 1031. doi:10.1039/jr9390001031González, M. A., Clark, J., Connelly, M., & Rivas, F. (2014). Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group. Bioorganic & Medicinal Chemistry Letters, 24(22), 5234-5237. doi:10.1016/j.bmcl.2014.09.061Balasubramanian, A., Teramoto, T., Kulkarni, A. A., Bhattacharjee, A. K., & Padmanabhan, R. (2017). Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus. Antiviral Research, 137, 141-150. doi:10.1016/j.antiviral.2016.11.015Roa-Linares, V. C., Brand, Y. M., Agudelo-Gomez, L. S., Tangarife-Castaño, V., Betancur-Galvis, L. A., Gallego-Gomez, J. C., & González, M. A. (2016). Anti-herpetic and anti-dengue activity of abietane ferruginol analogues synthesized from (+)-dehydroabietylamine. European Journal of Medicinal Chemistry, 108, 79-88. doi:10.1016/j.ejmech.2015.11.009González, M. A., & Pérez-Guaita, D. (2012). Short syntheses of (+)-ferruginol from (+)-dehydroabietylamine. Tetrahedron, 68(47), 9612-9615. doi:10.1016/j.tet.2012.09.055Dea-Ayuela, M. A., Bilbao-Ramos, P., Bolás-Fernández, F., & González-Cardenete, M. A. (2016). Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives. European Journal of Medicinal Chemistry, 121, 445-450. doi:10.1016/j.ejmech.2016.06.004Cory, A. H., Owen, T. C., Barltrop, J. A., & Cory, J. G. (1991). Use of an Aqueous Soluble Tetrazolium/Formazan Assay for Cell Growth Assays in Culture. Cancer Communications, 3(7), 207-212. doi:10.3727/095535491820873191Chattopadhyay, D., Sarkar, M. C.-, Chatterjee, T., Sharma Dey, R., Bag, P., Chakraborti, S., & Khan, M. T. H. (2009). Recent advancements for the evaluation of anti-viral activities of natural products. New Biotechnology, 25(5), 347-368. doi:10.1016/j.nbt.2009.03.00

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies

[EN] The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SWI573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species (L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABA(A) receptors (alpha(1)beta(2)gamma(2s)) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.Financial support by the Spanish Government [Consejo Superior de Investigaciones Cientificas (2016801008)] is gratefully acknowledged. M.S. thanks the support by the doctoral program "Molecular Drug Targets" (Austrian Science Fund FWF W 1232). F.R thanks the American Lebanese Syrian Associated Charities (ALSAC). M.A.D.-A. thanks the Santander Bank for the support for her project in consolidable groups of CEU-UCH.Hamulic, D.; Stadler, M.; Hering, S.; Padron, JM.; Bassett, R.; Rivas, F.; Loza-Mejia, M.... (2019). Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies. Journal of Natural Products. 82(4):823-831. https://doi.org/10.1021/acs.jnatprod.8b00884S82383182

Synthesis of bodinieric acids A and B, both C-18 and C-19-functionalized abietane diterpenoids: DFT study of the key aldol reaction

[EN] The first synthesis of C-18- and C-19-bifunctionalized abietane diterpenoids, bodinieric (or callicapoic) acids, via an aldol reaction has been developed. This key aldol reaction was very sensitive to steric hindrance. This fact has been studied by deuterium exchange experiments and DFT methods. Optimization of this reaction led to the synthesis of anti-inflammatory bodinieric acids A and B, starting from abietic acidFinancial support has been provided by the Spanish Government [CSIC (201680I008)] and the Universidad de Valencia, SpainZaragoza, RJ.; González-Cardenete, MA. (2020). Synthesis of bodinieric acids A and B, both C-18 and C-19-functionalized abietane diterpenoids: DFT study of the key aldol reaction. RSC Advances. 10(25):15015-15022. https://doi.org/10.1039/d0ra02711aS1501515022102

Anticoronavirus Evaluation of Antimicrobial Diterpenoids: Application of New Ferruginol Analogues

The abietane diterpene (+)-ferruginol (1), like other natural and semisynthetic abietanes, is distinguished for its interesting pharmacological properties such as antimicrobial activity, including antiviral. In this study, selected C18-functionalized semisynthetic abietanes prepared from the commercially available (+)-dehydroabietylamine or methyl dehydroabietate were tested in vitro against human coronavirus 229E (HCoV-229E). As a result, a new ferruginol analogue caused a relevant reduction in virus titer as well as the inhibition of a cytopathic effect. A toxicity prediction based on in silico analysis was also performed as well as an estimation of bioavailability. This work demonstrates the antimicrobial and specifically antiviral activity of two tested compounds, making these molecules interesting for the development of new antivirals.The funds were granted by the Universitat Politècnica de Valencia (grant ADSIDEO AD 1902 to M.A.G.-C) and the Université de Lorraine and CNRS (M.V.). The project was partially supported by the Erasmus+ Programme of the European Union, Key Action 2: Strategic Partnerships, Project No. 2020-1-CZ01-KA203-078218

Anticoronavirus Evaluation of Antimicrobial Diterpenoids: Application of New Ferruginol Analogues

The abietane diterpene (+)-ferruginol (1), like other natural and semisynthetic abietanes, is distinguished for its interesting pharmacological properties such as antimicrobial activity, including antiviral. In this study, selected C18-functionalized semisynthetic abietanes prepared from the commercially available (+)-dehydroabietylamine or methyl dehydroabietate were tested in vitro against human coronavirus 229E (HCoV-229E). As a result, a new ferruginol analogue caused a relevant reduction in virus titer as well as the inhibition of a cytopathic effect. A toxicity prediction based on in silico analysis was also performed as well as an estimation of bioavailability. This work demonstrates the antimicrobial and specifically antiviral activity of two tested compounds, making these molecules interesting for the development of new antivirals

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

The semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.Financial support by the Spanish Government [Consejo Superior de Investigaciones Científicas (201680I008)] is gratefully acknowledged. M. S. thanks the doctoral program “Molecular Drug Targets” (Austrian Science Fund FWF W 1232) for support.Peer reviewe