Development of novel valerolactam-benzimidazole hybrids anthelmintic derivatives: Diffusion and biotransformation studies in helminth parasites (original) (raw)
Related papers
Synthesis and Anthelmintic Evaluation of Novel Valerolactam- Benzimidazole Hybrids
Letters in Drug Design & Discovery, 2013
Some novel valerolactam derivatives of 5(6)-substituted-(1H-benzimidazol-2-yl-amine) were constructed based on the union of two structural domains with anthelmintic activity. The tested hybrid compounds 7-9 exhibited greater activity using the Nippostrongylus brasiliensis physiology-based in vitro bioassay in comparison to commercial anthelmintic benzimidazoles. Moreover, the improved physicochemical properties of hybrid compounds compared with valerolactam domain allowed the penetration of parasite barriers, concurrently with an increased intraparasitary bioavailability.
Drug transport mechanisms in helminth parasites: Passive diffusion of benzimidazole anthelmintics
Experimental Parasitology, 2006
Anthelmintic molecules must reach their receptors inside target parasites to exert the pharmacological eVect. Available data suggest that the main route of entry of antiparasitic drugs into helminth parasites would be through their external surface. However, it is unclear if trans-tegumental/cuticular penetration is the most important way of entry of benzimidazole (BZD) anthelmintics into their target parasites compared to oral ingestion. The relative involvement of active and passive transport mechanisms has not been deWned. The goal of the work reported here was to determine the main processes involved in the entry of BZD anthelmintic molecules into the three main classes of helminth parasites. Adult specimens of Moniezia benedeni (cestode), Fasciola hepatica (trematode) and Ascaris suum (nematode) were incubated in Kreb's Ringer Tris buVer (pH 7.4, 37°C) (1 g parasite/10 ml incubation medium) for 15, 45, and 90 min, respectively, in the presence of a concentration gradient of either fenbendazole (FBZ), oxfendazole or triclabendazole sulphoxide (TCBZSO) (1-30 mol/ ml, n D 4). Dead helminth specimens were also incubated with the same drug concentration gradient. Specimens of F. hepatica with the oral route closed oV by ligation were incubated with TCBZSO in the presence or absence of bovine serum albumin. After the incubation time elapsed, samples of parasite material were chemically extracted and prepared for high performance liquid chromatography analysis to measure drug/metabolite concentrations. Equivalent drug concentrations were measured within ligated and non-ligated liver Xukes, demonstrating that BZD do mainly penetrate by trans-tegumental diVusion. The higher the concentration of BZD molecules in the incubation medium, the greater their concentration recovered within the helminth parasites. High correlation coeYcients (>0.98) were obtained between initial drug concentration in the incubation medium and those measured inside the nematode, cestode, and trematode parasites. FBZ concentrations recovered from tissues of dead cestodes/nematodes over time were signiWcantly greater compared to those measured in living parasites. These diVerences in drug diVusion may be related to the morphological/functional properties of the parasite's external surfaces. The outcome of the work reported here indicates that passive drug transfer through the external helminth surface is the main transport mechanism accounting for BZD accumulation into target parasites.
Biopharmaceutic evaluation of novel anthelmintic (1H-benzimidazol-5(6)-yl)carboxamide derivatives
International journal of pharmaceutics, 2007
Benzimidazole 2-carbamates, such as albendazole (ABZ) and mebendazole (MBZ), used for the treatment of helmintic infections, have low aqueous solubility and poor bioavailability, both of which lead to high interindividual variability when used for human systemic helmintiosis; therefore, it is necessary to search for new anthelmintics with better biopharmaceutical properties. In the present study the solubility, pKa, logP and apparent permeability in the Caco-2 cells system of four novel anthelmintic (1H-benzimidazol-5(6)-yl)carboxamide derivatives (compounds 1-4) with a 2-methylthyo group were evaluated. Also the pharmacokinetic parameters of compound 1 which in previous studies showed activity similar to ABZ against T. spirallis, was evaluated in BALB/c mice, as a representative molecule of the series. The novel anthelmintics, showed better solubility than ABZ in aqueous acid pH and in organic solvents. The logP, P(app) and Caco-2 data indicate that the 4 derivatives are highly per...
2022
Soil-transmitted helminths (STHs) including Ascaris, hookworm, and whipworm are major human pathogens infecting over a billion people worldwide 1,2. There are few existing classes of anthelmintics and resistance is increasing 3-5-there is thus an urgent need for new classes of these drugs. Here we focus on identifying compounds that interfere with the unusual anaerobic metabolism that STHs use to survive the highly hypoxic conditions of the host gut 6-9. This requires rhodoquinone (RQ), a quinone electron carrier that is not made or used by the STH hosts 10. We previously showed that C. elegans also uses this rhodoquinone-dependent metabolism (RQDM) 11 and established a high throughput assay for RQDM 11. We screened a collection of 480 natural products for compounds that kill worms specifically when they rely on RQDM-these 480 are representatives of a full library of ~25,000 natural products and derivatives 12,13. We identify several classes of compound including a novel family of species selective inhibitors of Complex I. These Complex I inhibitors are based on a benzimidazole core but unlike commercial benzimidazole anthelmintics they do not target microtubules 14-17. We screened over 1,200 benzimidazoles and identify the key structural requirements for species selective Complex I inhibition. We suggest that these novel benzimidazole speciesselective Complex I inhibitors may be potential anthelmintics. Intro Soil-transmitted helminths (STHs from here on) are major pathogens of humans and livestock 1,2. Over a billion humans are infected by STHs including roundworm (Ascaris lumbricoides, hookworm (Necator americanus and Anclyostoma duodenale), and whipworm (Trichuris trichiura). These infections result in malnutrition, malaise and weakness, and can cause developmental defects and impaired growth in children 18. In addition, STHs infect a high proportion of livestock leading to reduced yield. This is a particular problem in poorer
A new class of anthelmintics effective against drug-resistant nematodes
Nature, 2008
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics-the benzimidazoles, imidazothiazoles and macrocyclic lactones-has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
Synthesis and anthelmintic potential of a novel series of 2-mercaptobenzimidazolopeptides
Biosciences, Biotechnology Research Asia, 2016
A novel series of 1,2-disubstituted benzimidazole derivatives was synthesized by coupling 2-mercaptobenzimidazol-1-acetic acid with various amino acid methyl ester hydrochlorides/dipeptides/ tripeptides using dicyclohexylcarbodiimide as the coupling agent and triethylamine as the base. All newly synthesized compounds were characterized by spectral as well as elemental analysis and evaluated for their anthelmintic potential. Compounds 6, 7 and 10 were found to exhibit potent activity against three earthworm species M. konkanensis, P. corethruses and Eudrilus sp. in comparison to mebendazole at 2 mg/ml dose level. Hydrolyzed benzimidazolopeptide analogs were found to be more potent than corresponding ester derivatives.
In Silico Design And ADME Study Of Novel Benzimidazole Containing Derivatives As Anthelmintic Agents
International Journal in Pharmaceutical Sciences, 2023
Benzimidazole derivative are very useful intermediates or subunits of the development of pharmaceutical or biological interest. Benzimidazole derivative are an important class of bioactive molecules in the field of drugs and pharmaceuticals. It is worth noting that most of the different chemical derivatives of benzimidazole play an effective and critical role in the medical field as a distinct treatment for many different diseases, for example anti-all types of infections. Albendazole is an anthelmintic that was recommended by the WHO to treat soil transmitted helminth infections. ABZ shows a broad spectrum of activity in domestic animals and was subsequently licensed for human use in 1982.Because of its effectiveness, safety and low price, ABZ is one of the main drugs used in PC programs. The excellent safety record of ABZ is related to its mechanism of action, which involves selective binding to ?tubulin and disruption of microtubule polymerization. Computer models are suitable substitutes for experimentation in such cases. The ten compounds were virtually screened with the protein target (PDB Code: 7ERI) to find potential lead candidates based on docking scores and residual interactions using molecular docking experiments. Lastly, the compounds' physicochemical characteristics were created in order to investigate their drug-likeness and pharmacokinetic profiles.