Mucosal responses to helminth infections
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
There are various anthelmintic drugs used to clear STH in man. Currently the most commonly used are the benzimidazoles, albendazole and mebendazole. Both drugs work relatively well against A. lumbricoides, while only albendazole shows good efficacy against hookworm. For the whipworm, T. trichiura, both drugs show relatively poor cure rates. This group of drugs works by disrupting the tubulin-microtubule system in cells, particularly β-tubulin, which results in parasites being unable to survive effectively in their chosen intestinal niche. Unfortunately, as demonstrated extensively from studies in animals, particularly domestic stock, the extensive use of these drugs drives resistance. It is generally agreed that changes in parasite β-tubulin are the basis for the resistance observed in gut-dwelling nematodes. Changes to the structure of the molecule driven through mutations to the β-tubulin gene result in structural alterations resulting in the failure of benzimidazoles to bind their target sites or have decreased binding efficiency. Other anthelmintic groups such as the nicotinic agonists (e.g., pyrantel) that target nicotinic acetylcholine (Ach)–gated cation channels found at the parasite's neuromuscular junctions are also used but generally have no better efficacy and again generate drug resistance.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Bhambra et al. (2016) reported the synthesis of a small library of 2,6-disubstituted-4,5,7- trifluorobenzothiophenes. Compounds 103 and 104 (Figure 37) demonstrated attractive antitrypanosomal activity against T. b. rhodesiense with IC50 values 0.60 and 0.53 μM, respectively, and no toxicity to mammalian cells. It is apparent that the activity of these compounds can be attributed to the existence of the benzimidazole moiety since its replacement resulted in loss of activity. Structures of potential hits 103 and 104.
Thiabendazole and Flubendazole
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Thiabendazole, also known as tiabendazole, is a benzimidazole anthelmintic synthesized in 1961 by Merck Sharpe & Dhome. It was the original “benzimidazole” anthelmintic, with several hundred analogs being developed in subsequent years by animal health companies. About 20 of these were eventually approved for animal use, of which five (albendazole, mebendazole, triclabendazole, thiabendazole, and flubendazole) were eventually developed and approved for human use. Although it remains commercially available as Mintezol (MSD), its availability is currently very limited owing to its toxicity and the availability of more effective and safer compounds. Thiabendazole is a white, odorless powder that is insoluble in water and only slightly soluble in alcohol. It has the chemical formula -2-(4′-thiazolyl)benzimidazole (C10H7N3S) with a molecular weight of 201.3. Its molecular structure is shown in Figure 202.1.
Novel therapeutic opportunities for Toxoplasma gondii, Trichomonas vaginalis, and Giardia intestinalis infections
Published in Expert Opinion on Therapeutic Patents, 2023
Francesca Arrighi, Arianna Granese, Paola Chimenti, Paolo Guglielmi
Giardia intestinalis infection shares with T. vaginalis the employment of the 5-nitroimidazole class for its management, albeit no standardized treatment is still recommended for giardiasis [25]. Another class of drugs employed in giardiasis treatment is benzimidazoles, with albendazole and mebendazole being the most used ones (Figure 2) [58]. Even in this case, the employment of these drugs is not devoid of side effects; over the above reported ones for 5-nitroimidazoles, benzimidazoles, often employed in a single dose for 7 days, provoke side effects such as nausea, vomiting, diarrhea, and abdominal pain, and its use requires attention during pregnancy because it could have teratogenic outcomes. Along with side effects, multiple resistance mechanisms have developed. In the light of the above, the search for novel effective drugs able to eradicate trichomoniasis as well as giardiasis is still an urgent need.
Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Abeer H. A. Abdelhafiz, Rabah A. T. Serya, Deena S. Lasheen, Nessa Wang, Mansour Sobeh, Michael Wink, Khaled A. M. Abouzid
Benzimidazole is a privileged scaffold which is incorporated in various bioactive compounds that reveal a wide range of biological activities and commonly used as anticancer, antihypertensive, antiviral, antifungal and anti-HIVs agents17. The benzimidazole scaffold is frequently used in many anticancer agents18,19 (Figure 2) such as bendamustine (4)20. Also, several benzmidazole based compounds exhibited an anticancer activity such as albendazole (5)21, carbendazim (6)22, tilomisole (Wy-18,251) (7)23. Moreover, some 2-substituted benzimidazole derivatives such as (8–10)24, (11)25 and (12)26 displayed a well tolerated anticancer activity in the cytotoxicity assays. Remarkably, the potent antiproliferative activity of the 2-(benzimidazol-2-yl)thio derivative (11) was apparent against colon cancer cells25. Interestingly, the 2,5-disubstituted benzimidazole derivative BD9L1 (12) displayed a substantial antiproliferative effects across a panel of cancer cell lines mainly CCRF/CEM leukaemia cells26.
Conformational restriction of a type II FMS inhibitor leading to discovery of 5-methyl-N-(2-aryl-1H-benzo[d]imidazo-5-yl)isoxazole-4-carboxamide analogues as selective FLT3 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Daseul Im, Hyungwoo Moon, Jingwoong Kim, Youri Oh, Miyoung Jang, Jung-Mi Hah
Type II FMS inhibitors consist of three parts, a hydrogen-bonding hinge, a central phenyl ring, and a secondary hydrophobic aromatic ring that facilitates binding to the DFG pocket13. Amide or urea linkages connect the middle phenyl ring and secondary hydrophobic aromatic ring. In the present study, we utilised conformational restriction of the connection to synthesise a novel heterocyclic scaffold (Figure 2). Specifically, we utilised a benzimidazole group as a rigid substitute for the middle phenyl ring-amide-secondary hydrophobic aromatic ring. Benzimidazole is a well-known privileged structure in medicinal chemistry that exhibits diverse biological activities14. Through our introduction of this structure into our in-house type II kinase inhibitor, we identified several novel FLT3 inhibitors with improved selectivity.
Related Knowledge Centers
- Aromaticity
- Benzene
- Imidazole
- Organic Compound
- Cyanocobalamin
- O-Phenylenediamine
- Trimethyl Orthoformate
- Coordination Complex
- Persistent Carbene
- Angiotensin II Receptor Blocker