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Draft:Hybrid molecule

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A hybrid molecule is a compound obtained by combination of two (or more) pharmacophores by covalent bond that is either designed to interact with multiple targets, improve the biological properties or enhance the efficacy of the compound.[1] The synthesis of hybrid molecules is an essential approach in the seeking of novel biologically active compounds for therapeutics.[2] This approach has found extensive applications in pharmacological field to overcome obstacles in pharmacokinetic, toxicity, side effects on current conventional drugs, and reduce the risk of developing resistance in cancer cells.[3]

Chemical Structures

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The hybrid molecules could be a combination of two natural products or natural product pharmacophore incorporated with synthetized group molecules.[4] In general, the structures of hybrid molecule is consist of two (or more) compounds or drugs that connected covalently by either functional group, or linker which could classified as followed:[5]

  1. Directly linked hybrid compound: each molecule is connected via a functional group.
  2. Merged or overlapped hybrid compound: these hybrid compound has a significant difference of the structure compared to the parental compounds which as consequences form overlapping structural motifs of two molecules/drugs.
  3. Linker associated hybrid compound: the hybrid molecules are connected by linker to attached two constituents that have possibility to have cleavable and non-cleavable properties. The cleavable linker will be biotransformed as soon as the hybrid gets into the active site while a non-cleavable linker maintains its structure aims to retain the biological activity.[6][7]

Pharmacological properties

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The biological properties of hybrid molecules particularly described exhibiting anti-cancer, anti-microbial, and anti-malarial activities.[8] The podophyllotoxin-artesunate hybrid showed a significant inhibition against HepG2 (liver cancer cell), A549 (lung cancer cell), HeLa (cervix cancer cell), and K562 (leukemia cell) and the activities is comparable to that etoposide which it already used as cancer chemotherapy.[9][10] Neomycin B-ciprofloxacin hybrids with an aromatic triazole linker and aliphatic triazole linker exhibited more potent activity than (free) neomycin B which has a potential as antibacterial agent.[11] Another example of hybrids of cinnamic acid and chalcones showed promising antimalarial activity against Plasmodium falciparum were found to be more potent than standard drug chloroquine.[12]

Challenges

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Despite the advantages and the escalating impact of hybrid molecules in medicinal area, this strategy also has potential limitations. The major problem of hybrid molecules is the large of its molecular weight (i.e. >500 Da) especially if the compound connected by a linker which possibility has a poor bioavailability and lower solubility.[13] Another challenge in research of hybrid molecules is the favored covalent bonding between two molecules is apart from the pharmacophores region in order to maintain it bioactivity. While modification any groups in pharmacophoric area could adversely affect the biological properties also possibility to have unexpected new binding target.[14]

References

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  1. ^ Mishra, Sahil; Singh, Palwinder (November 2016). "Hybrid molecules: The privileged scaffolds for various pharmaceuticals". European Journal of Medicinal Chemistry. 124: 500–536. doi:10.1016/j.ejmech.2016.08.039. PMID 27598238.
  2. ^ Zhang, Qianwen; Hui, Min; Chen, Guo; Huang, Huijing; Wang, Shiyu; Ye, Yanfei; Wang, Yan; Wang, Mengying; Zhang, Shuyuan; Huang, Lehao; Zhang, Fangjun; Liu, Zhiguo (3 April 2024). "Curcumin-Piperlongumine Hybrid Molecule Increases Cell Cycle Arrest and Apoptosis in Lung Cancer through JNK/c-Jun Signaling Pathway". Journal of Agricultural and Food Chemistry. 72 (13): 7244–7255. doi:10.1021/acs.jafc.4c00882. PMID 38517372.
  3. ^ Mancini, Ines; Vigna, Jacopo; Sighel, Denise; Defant, Andrea (3 August 2022). "Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents". Molecules. 27 (15): 4948. doi:10.3390/molecules27154948. PMC 9370406. PMID 35956896.
  4. ^ Mishra, Sahil; Singh, Palwinder (November 2016). "Hybrid molecules: The privileged scaffolds for various pharmaceuticals". European Journal of Medicinal Chemistry. 124: 500–536. doi:10.1016/j.ejmech.2016.08.039. PMID 27598238.
  5. ^ Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Sonawane, Pankaj; Paliwal, Harshali; Thareja, Suresh; Pathak, Prateek; Grishina, Maria; Jaremko, Mariusz; Emwas, Abdul-Hamid; Yadav, Jagat Pal; Verma, Amita; Khalilullah, Habibullah; Kumar, Pradeep (28 August 2022). "Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids". Pharmaceuticals. 15 (9): 1071. doi:10.3390/ph15091071. PMC 9500727. PMID 36145292.
  6. ^ Alkhzem, Abdulaziz H.; Woodman, Timothy J.; Blagbrough, Ian S. (2022). "Design and synthesis of hybrid compounds as novel drugs and medicines". RSC Advances. 12 (30): 19470–19484. Bibcode:2022RSCAd..1219470A. doi:10.1039/D2RA03281C.
  7. ^ Decker, M. (2011). "Hybrid Molecules Incorporating Natural Products: Applications in Cancer Therapy, Neurodegenerative Disorders and Beyond". Current Medicinal Chemistry. 18 (10): 1464–1475. doi:10.2174/092986711795328355. PMID 21428895.
  8. ^ Mishra, Sahil; Singh, Palwinder (November 2016). "Hybrid molecules: The privileged scaffolds for various pharmaceuticals". European Journal of Medicinal Chemistry. 124: 500–536. doi:10.1016/j.ejmech.2016.08.039. PMID 27598238.
  9. ^ Xiao, Jiaqi; Gao, Meixiang; Sun, Zhou; Diao, Qiang; Wang, Peng; Gao, Feng (December 2020). "Recent advances of podophyllotoxin/epipodophyllotoxin hybrids in anticancer activity, mode of action, and structure-activity relationship: An update (2010–2020)". European Journal of Medicinal Chemistry. 208: 112830. doi:10.1016/j.ejmech.2020.112830. PMID 32992133.
  10. ^ Zhang, Lei; Chen, Fan; Zhang, Zeguo; Chen, Yongzheng; Wang, Jing (January 2016). "Synthesis and biological evaluation of a novel artesunate–podophyllotoxin conjugate as anticancer agent". Bioorganic & Medicinal Chemistry Letters. 26 (1): 38–42. doi:10.1016/j.bmcl.2015.11.042. PMID 26615886.
  11. ^ Alkhzem, Abdulaziz H.; Woodman, Timothy J.; Blagbrough, Ian S. (2022). "Design and synthesis of hybrid compounds as novel drugs and medicines". RSC Advances. 12 (30): 19470–19484. Bibcode:2022RSCAd..1219470A. doi:10.1039/D2RA03281C.
  12. ^ Patel, Kuldeep; Karthikeyan, Chandrabose; Hari Narayana Moorthy, N. S.; Deora, Girdhar Singh; Solomon, Viswas Raja; Lee, Hoyun; Trivedi, Piyush (August 2012). "Design, synthesis and biological evaluation of some novel 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones as antimalarial agents". Medicinal Chemistry Research. 21 (8): 1780–1784. doi:10.1007/s00044-011-9694-1.
  13. ^ Serafin, Pawel; Kleczkowska, Patrycja (7 November 2023). "Bombesins: A New Frontier in Hybrid Compound Development". Pharmaceutics. 15 (11): 2597. doi:10.3390/pharmaceutics15112597. PMID 38004575.
  14. ^ Alkhzem, Abdulaziz H.; Woodman, Timothy J.; Blagbrough, Ian S. (2022). "Design and synthesis of hybrid compounds as novel drugs and medicines". RSC Advances. 12 (30): 19470–19484. Bibcode:2022RSCAd..1219470A. doi:10.1039/D2RA03281C.
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