Naturally occurring and biotechnologically accessed mectins 1 [1-4] (Figure 1) are magic bullet insecticides, acaricides, and antiviral agents that can be hydrolytically converted into monoglycosides 2 and aglycones 3 [5-7]. These compounds are used in the case of numerous diseases, ranging from cancer to those that affect antiparasitic, antibacterial, antifungal, antiviral, and anti-covid drugs. Compounds 1-3 contain reactive OH groups and double bonds, which can be chemically modified to give new biologically active compounds [8,9].
Figure 1. Compounds 1-12.
The selective reaction of the 5-OH group in compounds 1–3 with acid chlorides, anhydrides, isocyanates, and TBDMS chloride gives compounds 4-6 in preparative yields [10]. Complete acylation of 1-6 allows us to obtain compounds 7-9, whose molecules contain identical and different pendant functional groups. The removal of the TBDMS protecting group from the corresponding compounds 7-9 provides monoesters 10-12 bearing the OH group in position 5.
Life Chemicals’s interest in mectins resulted in the synthesis of more than 250 compounds of types 2-12 available from our stock Compound Collection. Moreover, we will be happy to carry out pioneering custom synthesis of virtual mectin-based libraries to meet your needs.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
Parasitic diseases have long hounded humankind, constituting a significant health problem. Their treatment was radically changed by three 2015 Nobel Prize Laureates in Physiology or Medicine. The Prize was awarded with one half jointly to Dr. William C. Campbell and Professor Satoshi Ōmura for their discoveries related to Avermectin, a groundbreaking therapy against infections caused by roundworm parasites, and the other half to Professor Tu Youyou for her discoveries concerning Artemisinin, a novel therapy against Malaria.
Today, the Avermectin derivative Ivermectin (Fig.1) has revolutionized the treatment of River Blindness and Lymphatic Filariasis, and Artemisinin-based drug combination therapy has profoundly reduced the incidence and mortality of Malaria.
As stated above, our Mectin-based Screening Library can become an efficient tool for those who are striving at contributing to the global combat against parasitic diseases.
Figure 2. Examples of mectin derivative drugs.
Representative screening compounds from the Screening Library:
Mectins are known to act on glutamate chloride channel receptors (GluClR) of nematodes [11-12]. Activation of GluClR results in the inhibition of pharyngeal muscle cells and motor neurons of nematodes, causing death by paralysis or starvation [12-13]. Resistance to known drugs, such as invermectin, is an urgent problem that requires the development of new drugs [12]. Thus, the compounds presented in the library can be used as potential anthelmintics and pesticides.
Our cheminformatics team docked this proprietary Library of mectin-based compounds into the chlorine channel of the nematode glycine receptor. 170 mectin compounds sat in the binding site, 151 of them had a docking score lower than -4.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 3RIF
- Constraints: no
- Filters used: no
- Number of compounds selected: 151
Figure 3. Spatial structure binding site of the complex of MRP1 with lead docking molecule F3409-1016 (docking score = -11.664)
Reference:
- (a) Ivermectin and Abamectin; Campbell W. C. (Ed.); Springer: New York, 2011.
- Saraiva, R. G.; Dimopoulos, G. Nat. Prod. Rep. 2020, 37, 338-354.
- Varghese, F. S.; Kaukinen, P.; Gläsker, S.; Bespalov, M.; Hanski, L.; Wennerberg, K.; Kümmerer, B. M.; Ahola, T. Antiviral Res. 2016, 126, 117-124.
- Sharun, K.; Dhama, K.; Patel, S. K.; Pathak, M.; Tiwari, R.; Singh, B. R.; Sah, R.; Bonilla‑Aldana, D. K.; Rodriguez‑Morales, A. J.; Leblebicioglu, H. Ann. Clin. Microbiol. Antimicrob. 2020, 19, 23.
- Mrozik, H.; Eskola, P.; Arison, B. H.; Albers-Schoenberg, G.; Fisher, M. H. J. Org. Chem. 1982, 47, 489.
- Fuse, T.; Ikeda, I.; Kita, T.; Furutani, S.; Nakajima, H.; Matsuda, K.; Ozoe, F.; Ozoe, Y. Pesticide Biochem. Physiol. 2015, 120, 82.
- Zhao, J.-H.; Xu, X.-J.; Ji, M.-H.; Cheng, J.-L.; Zhu, G.-N. J. Agricul. Food Chem.2011, 59, 4836.
- Awasthi, A.; Razzak, M.; Al-Kassas, R.; Harvey, J.; Garg, S. Chem. Pharm. Bull. 2012, 60, 931.
- Zhang, J.; Nan, X.; Yu, H.-T.; Cheng, P.-L.; Zhang, Y.; Liu, Y.-Q.; Zhang, S.-Y.; Hu, G.-F.; Liu, H.; Chen, A.-L. Eur. J. Med. Chem. 2016, 121, 422.
- Vashchenko, I.; Veselovska, M.; Dolgonos, G. A.; Lukin, O.; Poyarkov, A.; Kiyenko, T.; Gleave, M. E.; Fetyukhin, V.; Shivanyuk, A.; Gentile, F.; Cherkasov, A. Tetrahedron2023, 149, 133713.
- Hibbs RE, Gouaux E. Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature. 2011;474(7349):54-60. doi:10.1038/nature10139
- Atif M, Estrada-Mondragon A, Nguyen B, Lynch JW, Keramidas A. Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus. PLoS Pathog. 2017;13(10):e1006663. Published 2017 Oct 2. doi:10.1371/journal.ppat.1006663
- Wolstenholme AJ. Glutamate-gated chloride channels. J Biol Chem. 2012;287(48):40232-40238. doi:10.1074/jbc.R112.406280