Hybrid molecule
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 the pharmacological field to overcome obstacles in pharmacokinetic properties, toxicity, side effects of current conventional drugs, and reduce the risk of developing resistance in cancer cells.[3]
Chemical Structures
The hybrid molecules could be a combination of two natural products or a natural product pharmacophore incorporated with synthesized group molecules.[4] In general, the structures of hybrid molecules consist of two (or more) compounds or drugs that are connected covalently by either a functional group or a linker, which can be classified as follows:[5]
- Directly linked hybrid compound: each molecule is connected via a functional group.
- Merged or overlapped hybrid compound: these hybrid compounds have a significant difference in structure compared to the parental compounds, which consequently forms overlapping structural motifs of two molecules/drugs.
- Linker-associated hybrid compound: the hybrid molecules are connected by a linker to attach two constituents that have the possibility of having 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 to retain the biological activity.[6][7]
Pharmacological properties
The biological properties of hybrid molecules are particularly described as exhibiting anti-cancer, anti-microbial, and anti-malarial activities.[8] The podophyllotoxin-artesunate hybrid showed significant inhibition against HepG2 (liver cancer cell), A549 (lung cancer cell), HeLa (cervix cancer cell), and K562 (leukemia cell), and the activities are comparable to that of etoposide, which is 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 potential as an antibacterial agent.[11] Another example of hybrids of cinnamic acid and chalcones showed promising antimalarial activity against Plasmodium falciparum and were found to be more potent than the standard drug chloroquine.[12]
Challenges
Despite the advantages and the escalating impact of hybrid molecules in the medicinal area, this strategy also has potential limitations. The major problem of hybrid molecules is their large molecular weight (i.e. >500 Da), especially if the compound is connected by a linker, which may result in poor bioavailability and lower solubility.[13] Another challenge in the research of hybrid molecules is that the favored covalent bonding between two molecules is apart from the pharmacophore region in order to maintain its bioactivity. While modification of any groups in the pharmacophoric area could adversely affect the biological properties and potentially lead to unexpected new binding targets.[14]
References
- ↑ 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.
- ↑ 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 Check
|pmid=value (help). - ↑ 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 Check
|pmc=value (help). PMID 35956896 Check|pmid=value (help). - ↑ 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.
- ↑ 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 Check
|pmc=value (help). PMID 36145292 Check|pmid=value (help). - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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 Check
|pmid=value (help). - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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 Check
|pmid=value (help). - ↑ 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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