In Silico Design And ADME Study Of Novel Benzimidazole Containing Derivatives As Anthelmintic Agents (original) (raw)
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Screening of a Benzimidazole Derivative for Anthelmintic Activity with "Rule of 5" Approach
Journal of Pharmaceutical Research International, 2022
Purpose: Synthetic chemistry is an important route to develop new therapeutics for every disease. The presented research is focusing on the design, synthesis, evaluation, and Lipinski’s rule approach for a new biologically active benzimidazole derivative. Methods: The synthesis comprises the reaction between lactic acid and o-phenylenediamine (OPD) to produce a corresponding product followed by self-condensation for obtaining a complex multiple. Results: The newly produced composite was found to hold weighty anthelmintic property when we compared the same with Albendazole(Standard drug). When the concentration of the desired compound increases paralysis as well as death time found to decreases respectively. 50µg/ml of the synthesized drug gave a time for paralysis is 30.43 ± 5.33 min & time for death is 0.56 ± 5.32 min. Conclusion: The synthesized final compound showed to have anthelmintic activity and its orally active property was also predicted from the Molinspiration software us...
The nematode Wuchereria bancrofti and Brugia malayi are the causative agents of Lymphatic Filariasis, which is one of the leading causes of permanent and long-term disability in the world. Tubulin protein being involved in many cellular functions is a crucial drug target for nematodes. To have structural insights of this protein, a three dimensional model of B. malayi β-tubulin protein (BmBTP) was built using homology modeling. Docking study was performed on a selected set of ten anti-filarial drugs such as Albendazol, Albendazol sulfoxide, Albendazol sulfone (ABZSOO), Benzimidazole, Carbofuran, Coumaphos, Diethylcarbamazine, Methiazole, Santonin, and Thiabendazole (TBZ) with BmBTP. The docking analysis revealed that Ser-138, Gly-10, and Cys-12 play the most critical role for H-bond interaction, whereas Thr-143, Gly-140, Gly-142, Gly-144, Gln-11, and Ala-9 make extensive van der Waal and hydrophobic contacts. The molecular dynamics (MD) simulation was performed using GROMACS4.0, at 3 ns in order to evaluate the overall stability of the BmBTP and anti-filarial drug complexes. The MD’s trajectories depict that the complexes of the BmBTP–ligand are stable throughout the simulation except for TBZ. ABZSOO formed the best and stable complex with BmBTP, whereas remaining ligands were found to be as moderate inhibitors.
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
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...
Synthesis and Evaluation of Novel Anthelmentic Benzimidazole Derivatives
ijrpc.com
2-substituted benzimidazole derivatives were synthesized, purified and characterized by means of TLC, Melting point, IR, 1 H NMR, Mass spectral analysis respectively. The study aimed at screening synthetic compound for anthelmintic activity. The anthelmintic activity of 2-substituted benzimidazole (2a-2d) compounds was evaluated for mean paralysis and mean death time.
Computational biology and chemistry, 2018
A series of 2-Cl-benzimidazole derivatives was synthesized and assessed for antibacterial activity. Antibacterial results indicated that compounds 2d, 2e, 3a, 3b, 3c, 4d and 4e showed promising activity against B. cerus, S. aureus and P. aeruginosa (MIC: 6.2 μg/mL) and excellent efficacy against E. coli (MIC: 3.1 μg/mL). Furthermore, compounds 3d and 3e displayed better activity (MIC: 3.1 μg/mL) than the reference drugs chloramphenicol and cycloheximide against gram positive and gram negative bacterial strains. The compounds 3d-e also showed better activity than the reference drug paromomycin against B. cerus and P. aeruginosa and showed similar inhibition pattern against S. aureus and E. coli. (MIC: 3.1 μg/mL). Studies on fractional inhibitory concentration (FIC) determination of compounds 1a-e, 2a-c, 4a-c and the reference antibiotic via combination approach revealed a synergistic effect as the MIC values were lowered up to / to / of the original MIC. In-vitro cytotoxicity study i...
Tuberculosis, colloquially referred to as TB, is a highly prevalent bacterial infection that persists as a substantial global health concern. The present article centers its attention on the comprehensive exploration of the synthesis, molecular docking, and molecular dynamic simulation investigations pertaining to substituted benzimidazole derivatives. Additionally, a meticulous assessment of their anti-TB activities is conducted. A series of twelve substituted benzimidazole derivatives (1–12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FT-IR, 1H-NMR, and Mass spectra. The Microplate Alamar Blue Assay (MABA) was used to evaluate the anti-mycobacterial activity of synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/ml) and 8 (MIC = 0.8 g/ml) demonstrated exceptional potential to inhibit M. tuberculosis compared to the stand...
SYNTHESIS, ANTIMICROBIAL AND ANTHELMINTIC ACTIVITY OF SOME NOVEL BENZIMIDAZOLE DERIVATIVES
The benzimidazoles are also known as benzoglyoxalines. Benzimidazole derivatives are very useful intermediates or subunits of the development of pharmaceutical or biological interest. Benzimidazole derivatives play vital role in biological field such as antimicrobial, antiviral, antidiabetic, and anticancer activity. Therapeutic significance of these clinically useful drugs in treatment of microbial infections encouraged the development of some more potent and significant compounds. With the purpose of finding new chemical entities with enhanced antimicrobial activity, series comprises 1 and 2-substituted-5nitrobenzimidazole derivatives were synthesized. The presence of specific functional group were analyzed by IR spectroscopy. The determination of structure for the synthesized compounds by 1 H NMR and mass spectroscopy. Antimicrobial activity against bacteria and fungi was studied. The anthelmintic activity was evaluated on adult Indian earth worm Pheretima posthuma. The results of preliminary biological tests showed that of these compounds showed significant antimicrobial activity and anthelmintic activity.
Borneo Journal of Pharmacy
Onchocerciasis is one of the major neglected tropical diseases caused by the filarial worm (Onchocerca volvulus), affecting an estimated population of about 37 million people living predominantly in tropical Africa. The major treatment approach has been based on the use of Ivermectin, which kills the microfilariae or the less effective Doxycycline targeting Wolbachia, endosymbiont of filarial nematodes. Flubendazole (FBZ) has proved effective in treating adult worms but with threatening adverse effects. Against this backdrop, therefore, a combined molecular docking study and pharmacokinetic screening were conducted on a series of benzimidazole-benzoxaborole hybrids to find more potent analogs with attributes that address the limitations of existing therapies. All the nineteen analogs were found to possess better docking scores than the reference drug (FBZ, Moldock scores = -120.466 and -125.359). The results of pharmacokinetic testing suggest that four molecules (14, 16, 19, and 20)...