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Synthesis, pharmacological and molecular docking investigations of 1,3,4-oxadiazole-5-thionyl derivatives of extracted cis-clerodane diterpenoid from Cistus monspeliensis

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Abstract

Two main products namely 18-hydroxy-cis-clerodan-3-ene-15-oic acid and 18-acetoxy-cis-clerodan-3-ene-15-oic acid were isolated from the extract of the plant Cistus monspeliensis. The 18-acetoxy acid converted to its mother 18-hydroxy acid in good yield. Other two 1,3,4- oxadiazole derivatives namely 5-((R)-4-((1S,2R,4aS,8aR)-5-(hydroxymethyl)-1,2,4a-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl)-2-methylbutyl)-1,3,4-oxadiazole-2(3H)-thione and 5-((R)-2-methyl-4-((1S,2R,4aS,8aR)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl)butyl)-1,3,4-oxadiazole-2(3H)-thione were synthesized from the obtained acid, characterized by infrared, 1H, 13C-NMR and mass spectroscopy. Their antioxidant power using the DPPH method showed interesting results compared with the reference ascorbic acid (IC50 = 16.30 μM). Their antibacterial activity on Gram-positive bacteria Staphylococcus aureus (ATCC 33862) and Bacillus cereus (ATCC 10876), and Gram-negative bacteria Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) showed that the resulting 1,3,4-oxadiazole thiones have interesting effects against both Gram-positive bacteria using amikacin as a positive reference. The anti-inflammatory activity investigation showed that both clerodane diterpenoid 1,3,4-oxadiazolyl-5-thionyl derivatives had higher inhibition effect on the nitric oxide production with IC50 NO values of 43.59 ± 1.8 and 18.64 ± 0.06 μM compared to that of diclofenac (IC50 NO = 73.30 ± 0.40 μM). Docking studies showed that the terpene skeleton of the starting material and both heterocycles form hydrophobic and H-bonds interactions with iNOS. The thione group of the C18-methyl oxadiazole forms a hydrogen bond with Met368, which may explain its highest anti-inflammatory activity.

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References

  1. Berti G, Livi O, Segnini D. Cistodiol and cistodioic acid, diterpenoids with a cis-fused clerodane skeleton. Tet Lett. 1970;11:1401–4. https://doi.org/10.1016/S0040-4039(01)97980-8

    Article  Google Scholar 

  2. Merritt AT, Ley SV. Clerodane diterpenoids. Nat Prod Rep. 1992;9:243–87. https://doi.org/10.1039/NP9920900243

    Article  Google Scholar 

  3. Kolocouris A, Mavromoustakos T, Demetzos C, Terzis A, Grdadolnik SG. Structure elucidation and conformational properties of a novel bioactive clerodane diterpene using a combination of high field NMR spectroscopy, computational analysis, and X-ray diffraction. Bio Med Chem Lett. 2001;11:837–40. https://doi.org/10.1016/s0960-894x(01)00072-5

    Article  Google Scholar 

  4. Guzmán B, Vargas P. Systematics, character evolution, and biogeography of Cistus L. (Cistaceae) based on ITS, trnL-trnF, and matK sequences. Mol Phyl Evol. 2005;37:644–60. https://doi.org/10.1016/j.ympev.2005.04.026

    Article  Google Scholar 

  5. Coello AJ, Fernández‐Mazuecos M, García‐Verdugo C, Vargas P. Phylogeographic sampling guided by species distribution modeling reveals the quaternary history of the Mediterranean-Canarian Cistus monspeliensis (Cistaceae). J Syst Evol. 2020;59:262–77. https://doi.org/10.1111/jse.12570

    Article  Google Scholar 

  6. Kalpoutzakis E, Aligiannis N, Skaltsounis AL, Mitakou S. cis-clerodane type diterpenes from Cistus monspeliensis. J Nat Prod. 2003;66:316–9. https://doi.org/10.1021/np0204388

    Article  Google Scholar 

  7. Güvenç A, Yıldız S, Özkan AM, Erdurak CS, Coşkun M, Yılmaz G, et al. Antimicrobiological studies on Turkish Cistus species. Pharm Biol. 2008;43:178–83. https://doi.org/10.1080/13880200590919537

    Article  Google Scholar 

  8. Fokialakis N, Kalpoutzakis E, Tekwani BL, Skaltsounis AL, Duke SO. Antileishmanial activity of natural diterpenes from Cistus sp. and semisynthetic derivatives thereof. Biol Pharm Bull. 2006;29:1775–8. https://doi.org/10.1248/bpb.29.1775

    Article  Google Scholar 

  9. Fadel H, Kebbi S, Chalchat JC, Figueredo G, Chalard P, Benayache F, et al. Identification of volatile components and antioxidant assessment of the aerial part extracts from an Algerian Cistus albidus L. of the Aures region. J N. Technol Mater. 2020;10:38–46. https://doi.org/10.12816/0058534

    Article  Google Scholar 

  10. Piccinelli AL, Mencherini T, Celano R, Mouhoubi Z, Tamendjari A, Aquino RP, et al. Chemical composition and antioxidant activity of Algerian Propolis. J Agric Food Chem. 2013;61:5080–8. https://doi.org/10.1021/jf400779w

    Article  Google Scholar 

  11. Dong B, Yang X, Liu W, An L, Zhang X, Tuerhong M, et al. Anti-inflammatory neo-clerodane diterpenoids from Ajuga pantantha. J Nat Prod. 2020;83:894–904. https://doi.org/10.1021/acs.jnatprod.9b00629

    Article  Google Scholar 

  12. Simpson BS, Luo X, Costabile M, Caughey GE, Wang J, Claudie DJ, et al. Polyandric acid A, a clerodane diterpenoid from the Australian medicinal plant Dodonaea polyandra, attenuates pro-inflammatory cytokine secretion in vitro and in vivo. J Nat Prod. 2014;77:85–91. https://doi.org/10.1021/np400704b

    Article  Google Scholar 

  13. Kitagawa I, Yoshihara M, Tani T, Yosioka I. Linaridial, a new cis-clerodane-type diterpene dialdehyde, from Linaria japonica miq. Tet Lett. 1975;1:23–26. https://doi.org/10.1016/S0040-4039(00)71767-9

    Article  Google Scholar 

  14. Huang Z, Jiang MY, Zhou ZY, Xu D. Two new clerodane diterpenes from Dodonaea viscosa. Z Naturforsh. 2010;65b:83–86. doi: 0932-0776/10/0100-0083

    Article  Google Scholar 

  15. Khalil NM, Sperotto JS, Manfron MP. Antiinflamatory activity and acute toxicity of Dodonaea viscosa. Fitoterapia. 2006;77:478–80. https://doi.org/10.1016/j.fitote.2006.06.002

    Article  Google Scholar 

  16. Patel M, Coogan MM. Antifungal activity of the plant Dodonaea viscosa var. angustifolia on Candida albicans from HIV-infected patients. J Ethnopharmacol. 2008;118:173–6. https://doi.org/10.1016/j.jep.2008.03.009

    Article  Google Scholar 

  17. Rodriguez AD, Yoshida WY, Paul J, Scheuer PJ. Popolohuanone A and B. two new sesquiterpenoid aminoquinones from a pacific sponge Dysidea sp. Tetrahedron 1990;46:8025–30. https://doi.org/10.1016/S0040-4020(01)81459-9

    Article  Google Scholar 

  18. Yoo HD, Leung D, Sanghara J, Daley D, Soest R, Andersen RJ. Isoarenarol, A new protein kinase inhibitor from the marine sponge Dysidea arenaria. Pharm Biol. 2003;41:223–5. https://doi.org/10.1076/phbi.41.4.223.15679

    Article  Google Scholar 

  19. Tian K, Li XL, Zhang L, Gan YY, Meng J, Wu SQ, et al. Synthesis of novel indole derivatives containing double 1,3,4‑oxadiazole moiety as efficient bactericides against phytopathogenic bacterium Xanthomonas oryzae. Chem Pap. 2018;73:17–25. https://doi.org/10.1007/s11696-018-0555-y

    Article  Google Scholar 

  20. Faldu VJ, Talpara PK, Bhuva NH, Vachharajani PR, Shah VH. Synthesis, characterization and biological evaluation of some newer 5-[6-chloro/fluoro/nitro-2-(p-chloro/fluoro/methyl phenyl)-quinolin-4-yl]-1,3,4-oxadiazole-2-thiols. Inter Lett Chem Phys Astron. 2014;25:25–32..

  21. Makane VB, Krishna VS, Krishna EV, Shukla M, Mahizhaveni B, Misra S, et al. Novel 1,3,4-oxadiazoles as antitubercular agents with limited activity against drug-resistant tuberculosis. Future Med Chem. 2019;11:499–10. https://doi.org/10.4155/fmc-2018-0378

    Article  Google Scholar 

  22. Yarmohammadi E, Beyzaei H, Aryan R, Moradi A. Ultrasound‑assisted, low‑solvent and acid/base‑free synthesis of 5‑substituted 1,3,4‑oxadiazole‑2‑thiols as potent antimicrobial and antioxidant agents. Mol Divers. 2021;25:2367–78. https://doi.org/10.1007/s11030-020-10125-y

    Article  Google Scholar 

  23. Taieb Brahimi F, Belkhadem F, Trari B, Othman AA. Diazole and triazole derivatives of castor oil extract: synthesis, hypoglycemic effect, antioxidant potential and antimicrobial activity. Grasas Aceites. 2020;71:e378 https://doi.org/10.3989/gya.0342191

    Article  Google Scholar 

  24. Radini IAM, Elsheikh TMY, El-Telbani EM, Khidre RE. New potential antimalarial agents: design, synthesis and biological evaluation of some novel quinoline derivatives as antimalarial agents. Molecules. 2016;21:909 https://doi.org/10.3390/molecules21070909

    Article  Google Scholar 

  25. Gudipati R, Reddy Anreddy RN, Manda S. Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-one derivatives. SA Pharm J. 2011;19:153–8. https://doi.org/10.1016/i.jsps.2011.03.002

    Article  Google Scholar 

  26. Pretsch E, Bühlmann P, Affolter C. Structure determination of organic compounds: tables of spectral data. Berlin: Springer; 2000. p. 7–12.

    Book  Google Scholar 

  27. Zaki RM, Abdul-Malik MA, Saber SH, Radwan SM, Kamal El-Dean AM. A convenient synthesis, reactions and biological evaluation of novel pyrazolo[3,4-b]selenolo[3,2-e]pyrazine heterocycles as potential anticancer and antimicrobial agents. Med Chem Res. 2020;25:2130–45. https://doi.org/10.1007/s00044-020-02635-z

    Article  Google Scholar 

  28. CASFM/EUCAST. Détermination de la sensibilité aux antibiotiques. Paris: Société Française de Microbiologie; 2019. p. 6–25.

    Google Scholar 

  29. Galisteo A, Jannus F, García-García A, Aheget H, Rojas S, Lupiañez JA, et al. Diclofenac N-derivatives as therapeutic agents with anti-inflammatory and anti-cancer effect. Int J Mol Sci. 2021;22:5067 https://doi.org/10.3390/ijms22105067

    Article  Google Scholar 

  30. Griess P. Bemerkungen zu der Abhandlung der H.H. Weselsky und Benedikt Ueber einige Azoverbindungen. Ber Dtsch Chem Ges. 1879;12:426–8.

    Article  Google Scholar 

  31. Sonar SA, Lal G. The iNOS activity during an immune response controls the CNS pathology in experimental autoimmune encephalomyelitis. Front Immunol. 2019;10:710 https://doi.org/10.3389/fimmu.2019.00710

    Article  Google Scholar 

  32. Grottelli S, Amoroso R, Macchioni L, D’Onofrio F, Fettucciari K, Bellezza I, et al. Acetamidine-based iNOS inhibitors as molecular tools to counteract inflammation in BV2 microglial cells. Molecules. 2020;25:2646 https://doi.org/10.3390/molecules25112646

    Article  Google Scholar 

  33. Koksal M, Dedeoglu-Erdogan A, Bader M, Gurdal EE, Sippl W, Reis R, et al. Design, synthesis, and molecular docking of novel 3,5-disubstituted-1,3,4-oxadiazole derivatives as iNOS inhibitors. Arch Pharm. 2021;354:2000469 https://doi.org/10.1002/ardp.202000469

    Article  Google Scholar 

  34. Wang JJ, Sun W, Jia WD, Bian M, Yu LJ. Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini-review. J Enzym Inhib Med Chem. 2022;37:2304–19. https://doi.org/10.1080/14756366.2022.2115036.

    Article  Google Scholar 

  35. Desai N, Monapara J, Jethawa A, Khedkar V, Shingate B. Oxadiazole: A highly versatile scaffold in drug discovery. Arch Pharm. 2022;355:2200123 https://doi.org/10.1002/ardp.202200123

    Article  Google Scholar 

  36. Faheem M, Althobaiti YS, Khan AW, Ullah A, Ali SH, Ilyas U. Investigation of 1, 3, 4 oxadiazole derivative in PTZ-induced neurodegeneration: a simulation and molecular approach. J Inflamm Res. 2021;14:5659–79. https://doi.org/10.2147/JIR.S328609

    Article  Google Scholar 

  37. Hong CH, Hur SK, Oh OJ, Kim SS, Nam KA, Lee SK. Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells. J Ethnopharmacol. 2002;83:153–9. https://doi.org/10.1016/s0378-8741(02)00205-2

    Article  Google Scholar 

  38. Zhong HJ, Liu LJ, Chong CM, Lu L, Wang M, Chan DSH, et al. Discovery of a natural product-like iNOS inhibitor by molecular docking with potential neuroprotective effects in vivo. PLoS One. 2014;9:e92905 https://doi.org/10.1371/journal.pone.0092905

    Article  Google Scholar 

  39. Kartasasmita R, Herowati R, Gusdinar T. Docking study of quercetin derivatives on inducible nitric oxide synthase and prediction of their absorption and distribution properties. J Appl Sci. 2010;10:3098–104. https://doi.org/10.3923/jas.2010.3098.3104

    Article  Google Scholar 

  40. Zhang H, Zan J, Yu G, Jiang M, Liu P. A Combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors. Int J Mol Sci. 2012;13:11210–27. https://doi.org/10.3390/ijms130911210

    Article  Google Scholar 

  41. Saleh RA, Mohammad HA, Saber SNA. New mixed ligand Cobalt(II), Nickel(II) and Copper(II) complexes of 2,2’-bipyridine-3,3’-dicarboxylic acid (bpdc) with 2-mercapto-5-phenyl-1,3,4-oxadiazole (phozSH) and their antioxidant activity. Orient J Chem. 2020;36:834–42. https://doi.org/10.13005/ojc/360506

    Article  Google Scholar 

  42. Turukarabettu V, Kalluraya B, Sharma M. Design and synthesis of sulfur cross-linked 1,3,4-oxadiazole-nitro(furan/thiophene)-propenones as dual inhibitors of inflammation and tuberculosis: molecular docking and Hirshfeld surface analysis. Monatsh Chem. 2019;150:1999–2010. https://doi.org/10.1007/s00706-019-02507-2

    Article  Google Scholar 

  43. Barba-Ostria C, Carrera-Pacheco SE, Gonzalez-Pastor R, Heredia-Moya J, Mayorga-Ramos A, Rodríguez-Pólit C, et al. Evaluation of biological activity of natural compounds: current trends and methods. Molecules 2022;27:4490 https://doi.org/10.3390/molecules27144490

    Article  Google Scholar 

  44. Balouiri M, Sadiki M, Koraichi IS. Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Anal. 2016;6:71–79. https://doi.org/10.1016/j.jpha.2015.11.005

    Article  Google Scholar 

  45. Pérez-Jiménez A, Rufino-Palomares EE, Fernández-Gallego N, Ortuño-Costela MC, Reyes-Zurita FJ, Peragón J, et al. Target molecules in 3T3-L1 adipocytes differentiation are regulated by maslinic acid, a natural triterpene from Olea europaea. Phytomedicine. 2016;23:1301–11. https://doi.org/10.1016/j.phymed.2016.07.001

    Article  Google Scholar 

  46. Reyes-Zurita FJ, Medina-O’Donnell M, Ferrer-Martin RM, Rufino-Palomares EE, Martin-Fonseca S, Rivas F, et al. The oleanolic acid derivative, 3-O-succinyl-28-Obenzyl oleanolate, induces apoptosis in B16-F10 melanoma cells via the mitochondrial apoptotic pathway. RSC Adv. 2016;6:93590–601. https://doi.org/10.1039/C6RA18879F

    Article  Google Scholar 

  47. Jannus F, Medina‐O’Donnell M, Neubrand VE, Marín M, Saez‐Lara MJ, Sepulveda MR, et al. Efficient in vitro and in vivo anti‐inflammatory activity of a diamine‐PEGylated oleanolic acid derivative. Int J Mol Sci. 2021;22:8158 https://doi.org/10.3390/ijms22158158

    Article  Google Scholar 

  48. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30:2785–91. https://doi.org/10.1002/jcc.21256

    Article  Google Scholar 

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Acknowledgements

This paper is dedicated to Pr. Adil Ali Othman for his retirement. The authors thank the European Commission for the scholarship Erasmus+ International Credit Mobility granted to Fatima I. Mahi.

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Authors and Affiliations

  1. Laboratoire de Synthèse Organique Bioactive, Département de Génie Chimique, Faculté de Chimie, Université des Sciences et de la Technologie d’Oran, Mohamed Boudiaf-USTOMB, BP. 1505, El-M’naouer, 31003, Oran, Algeria

    Fatima I. Mahi & Adil A. Othman

  2. Département de Génie Chimique, Faculté de Chimie, Université des Sciences et de la Technologie d’Oran, Mohamed Boudiaf-USTOMB, BP. 1505, El-M’naouer, 31003, Oran, Algeria

    Mohammed A. Mehdid

  3. Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, 18071, Granada, Spain

    Houda Zentar & Rachid Chahboun

  4. Chemistry Department, University of the Free State, P.O. Box 339, Bloemfontein, 9300, South Africa

    Az-eddine El Mansouri

  5. Laboratory of Applied Microbiology, Department of Biology, Faculty of Nature Sciences and Life, University of Ahmed Ben Bella 1, BP. 16. Es-Senia, 31100, Oran, Algeria

    Nisserine Hamini-Kadar

  6. Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, 18071, Granada, Spain

    Fernando J. Reyes-Zurita

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  1. Fatima I. Mahi
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Mahi, F.I., Mehdid, M.A., Zentar, H. et al. Synthesis, pharmacological and molecular docking investigations of 1,3,4-oxadiazole-5-thionyl derivatives of extracted cis-clerodane diterpenoid from Cistus monspeliensis. Med Chem Res 32, 128–143 (2023). https://doi.org/10.1007/s00044-022-02996-7

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