Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Synthesis, Characterization and Pharmacological Screening of Some Novel 2- substituted and 1(H)-substituted Benzimidazole Derivatives as potent Anti-cancer agents

The most of drugs containing Benzimidazole ring is a prominent structural motif found in numerous therapeutically active compounds. Benzimidazole and its synthetic analogues have been found to exhibit industrial, agricultural and biological application such as antitubercular, anti-inflammatory, analgesic, anticancer, anticoagulant, as well as good antifungal and anti microbial activity. Recent advances in technology considers microwave irradiation energy as the most efficient means of heating reactions for chemical transformations that can be accomplished in a minutes. Microwave irradiation assists organic synthesis (MAOS) not only helps in implementing green chemistry but also led to progress in organic synthesis. We report pharmacological screening of some novel 2 substituted and 1(h)-substituted Benzimidazole derivatives.

A Panoramic Review of Benzimidazole Derivatives and Their Potential Biological Activity

The therapeutic potential of the benzimidazole nucleus dates back to 1944, being and important heterocycle system due to its presence in a wide range of bioactive compounds such as antiviral, anticancer, antibacterial, and so on, where optimization of substituents in this class of pharmacophore has resulted in many drugs. Its extensive biological activity is due to its physicochemical properties like hydrogen bond donor-acceptor capability,  stacking interactions, coordination bonds with metals as ligands and hydrophobic interactions; properties that allow them to easily bind with a series of biomolecules, including enzymes and nucleic acids, causing a growing interest in these types of molecules. This review aims to present an overview to leading benzimidazole derivatives, as well as to show the importance of the nature and type of substituents at the N1, C2, and C5(6) positions, when they are biologically evaluated, which can lead to obtaining potent drug candidate with significant range of biological activities.

Advances of Benzimidazole Derivatives as Anticancer Agents: Bench to Bedside

Benzimidazole is one of the privileged nitrogen-containing scaffolds known for its versatile diversified role in insecticides, pesticides, dyes, pigments and pharmaceuticals. Due to its electron-rich environment, structural features and binding potency of various therapeutic targets, benzimidazole derivatives exhibit a broad spectrum of biological activity that majorly includes antimicrobial, antifungal, analgesics, anti-diabetic and anticancer agents. Several benzimidazole scaffolds bearing drugs are clinically approved; they are used for various indications. For example, Bilastine, Lerisetron, Maribavir and Nocodazole are the most widely used benzimidazole-based marketed drugs available as an antihistamine, antiviral and antimitotic agent, respectively. Another example is the recently approved anticancer drug Binimetinib and Selumetinib, which are indicated for BRAF mutated melanoma and plexiform neurofibromas. Not only this, many benzimidazole-based anticancer drugs are in late phases of clinical development. Due to the vast therapeutic potential of benzimidazole scaffold in cancer research, medicinal chemists have gained a lot of attraction to explore it more and develop novel, highly effective and target-specific benzimidazole-based potential anticancer drugs.

Synthesis and Molecular Modeling Studies of 2-[2-(3-nitrophenyl)-1h-benzimidazol-1-yl]-acetamide Derivatives as Anthelmintic

Benzimidazole derivatives of substituted 2 [2-(3-nitrophenyl)-1H-benzimidazole-1-yl] acetamide analogues were synthesized and studied for antihelminthic activity. Compounds 3a–o were obtained in three steps, starting with the Oxidative Condensation of the appropriate 3-nitrobenzaldeyde, o-phenylenediamine and sodium hydrogen sulfite to form 2-(3-nitrophenyl)-1H-benzimidazole (1a). In second step Nucleophilic substitution, Chlorine atom of ethylchloroacetate will attach on nitrogen of benzimidazole by replacing hydrogen with elimination of hydrochloric acid to form ethyl [2-(3-nitrophenyl)-1H-benzimidazole-1-Yl acetate (2a).In third step amide formation from ester takes place by substitution of electrophilic with loss of ethanol to form substituted 2 [2-(3-nitrophenyl)-1H-benzimidazole-1-yl] acetamide 3a–o The antihelminthic activity showed that compounds 3f, 3h, 3i, 3j and 3k good activity against Indian earthworms (Pheretima posthuma) in comparison to albendazole.

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.

Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity

Mebendazole and flubendazole are antihelmintic drugs that have re-entered the research spotlight due to their exhibited anticancer effects, thus making them strong candidates as repurposed drugs. However, these benzimidazole derivatives exhibit poor solubility in water and various organic solvents, which limits their bioavailability. With the aim of obtaining an improved drug solubility and increased biological effect, mebendazole and flubendazole were complexed with 2-hydroxypropyl-β-cyclodextrin (HPBCD). The binary 1:1 conjugates were physicochemically evaluated by X-ray diffraction, thermal analysis, and FTIR spectroscopy, revealing the formation of physical mixtures. The increased aqueous solubility of the binary 1:1 conjugates vs. pure benzimidazole compounds was demonstrated by performing dissolution tests. The in vitro antiproliferative activity of mebendazole and flubendazole, as well as their combination with HPBCD, was tested on two cancer cell lines, human melanoma—A375 and pulmonary adenocarcinoma—A549 by the MTT assay. The cytotoxic activity manifested in a dose-dependent manner while the presence of HPBCD increased the antiproliferative activity against the targeted cells. Treatment of A375 and A549 cell lines with the binary conjugates induced a significant inhibition of mitochondrial respiration, as revealed by high-resolution respirometry studies. Molecular docking analysis showed that one of the mechanisms related to MEB and FLU cytotoxic activity may be due to the inhibition of MEK/ERK proteins.