Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond

Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer—the most dreadful cancer so far

Mexican Medicinal Plants as an Alternative for the Development of New Compounds Against Protozoan Parasites

The protozoan parasites Plasmodium, Leishmania, Trypanosoma, Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis, cause high morbidity and mortality in developed and developing countries. P. falciparum is responsible for malaria, one of the most severe infectious diseases in Africa. Hundreds of million people are affected by Trypanosoma and Leishmania that cause African and South American trypanosomiasis, and leishmaniasis. E. histolytica and G. lamblia contribute to the enormous burden of diarrheal diseases worldwide; trichomoniasis is the most common nonviral sexually transmitted disease in the world. Because of the important side effects of current treatments and the decrease in drug susceptibility, there is a renewed interest for the search of therapeutic alternatives against these pathogens. Natural products obtained from medicinal plants and their derivatives have been recognized for many years as a source of therapeutic agents. There are numerous reports about medicinal plants that are used by indigenous communities to treat gastrointestinal complaints. Importantly, phytochemical studies have allowed the identification of several secondary metabolites with anti-parasite activity. Our review revealed that Mexican medicinal plants have a great potential for the identification of new molecules with activity against protozoan parasites of medical importance worldwide and their potential use as new therapeutic compounds

Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures

We describe the synthesis of 12 new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives on solid supports with room temperature and microwave-assisted solvent-free procedures. Results show that solid supports have good catalytic activity in the formation of quinoxaline 1,4-di-N-oxide derivatives. We found that florisil and montmorillonite KSF and K10 could be used as new, easily available, inexpensive alternatives of catalysts. Additionally, room temperature and microwave-irradiation solvent-free synthesis was more efficient than a conventional procedure (Beirut reaction), reducing reaction time and increasing yield

In vitro Evaluation of Phthalimide Derivatives Against Cancer Cell lines

Los cánceres de pulmón, próstata e hígado se encuentran entre los más prevalentes en los hombres. El cáncer de mama, de cuello uterino y de tiroides se encuentran entre los más prevalentes en mujeres (OMS, 2019). El tratamiento del cáncer generalmente incluye quimioterapia y radioterapia; sin embargo, los medicamentos contra el cáncer disponibles tienen una selectividad baja y causan efectos adversos graves, como nefrotoxicidad, neurotoxicidad y mielosupresión (Matsuo et al., 2010). Por tanto, el diseño y desarrollo de compuestos como nuevos agentes anticancerígenos frente a los tipos de cáncer de mayor incidencia son de vital importancia en el campo de la salud. Los derivados de ftalimida son compuestos prometedores para el desarrollo de nuevos agentes anticancerígenos (Li et al., 2011; Grigalius y Petrikaite, 2017; Kamal et al., 2002). Basado en lo anterior, Este trabajo tuvo como objetivo evaluar la actividad antiproliferativa de 43 derivados de ftalimida contra una línea celular de cáncer principal en hombres (HepG2) y dos líneas celulares de cáncer principales en mujeres (HeLa y 4T1). Además, se determinó la citotoxicidad de los compuestos contra una línea celular de fibroblasto murino normal (3T3). Los resultados mostraron que los compuestos C16, E11 y E16 presentaron la mejor actividad antiproliferativa contra las líneas celulares HeLa y 4T1. El compuesto H16 solo disminuyó la proliferación celular en un 32% contra la línea celular HepG2. Los compuestos H5, H16, E2, E16 y C1 no afectaron a la proliferación de la línea celular 3T3. Demostrando que sería importante continuar con el análisis de este tipo de compuestos frente a diferentes cánceres para encontrar nuevos compuestos con mejor actividad que los actualmente disponibles en el mercado

Synthesis and in vitro evaluation of new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide against Entamoeba histolytica

Biotecnologi

Medicinal bismuth: Bismuth-organic frameworks as pharmaceutically privileged compounds

Historically organometallic compounds have been used to cure certain diseases with limited applications. Although bismuth belongs to the category of heavy metals, many of its derivatives have found applications in modern drug discovery research, mainly because of its low toxicity and higher bioavailability. Being an eco-friendly mild Lewis acid, compounds having bismuth as a central atom are capable of binding several proteins in humans and other species. Bismuth complexes demonstrated antibacterial potential in syphilis, diarrhea, gastritis, and colitis. Apart from antibacterial activities, bismuth compounds exhibited anticancer, antileishmanial, and some extent of antifungal and other medicinal properties. This article discusses major synthetic methods and pharmacological potentials of bismuth complexes exhibiting in vitro activity to significant clinical performance in a systematic and timely manner

Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures

We describe the synthesis of 12 new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives on solid supports with room temperature and microwave-assisted solvent-free procedures. Results show that solid supports have good catalytic activity in the formation of quinoxaline 1,4-di-N-oxide derivatives. We found that florisil and montmorillonite KSF and K10 could be used as new, easily available, inexpensive alternatives of catalysts. Additionally, room temperature and microwave-irradiation solvent-free synthesis was more efficient than a conventional procedure (Beirut reaction), reducing reaction time and increasing yield

Theoretical and experimental study of polycyclic aromatic compounds as β-tubulin inhibitors

In this work, through a docking analysis of compounds from the ZINC chemical library on human β-tubulin using high performance computer cluster, we report new polycyclic aromatic compounds that bind with high energy on the colchicine binding site of β-tubulin, suggesting three new key amino acids. However, molecular dynamic analysis showed low stability in the interaction between ligand and receptor. Results were confirmed experimentally in in vitro and in vivo models that suggest that molecular dynamics simulation is the best option to find new potential β-tubulin inhibitors

Ligand-based virtual screening, molecular docking, and molecular dynamics of eugenol analogs as potential acetylcholinesterase inhibitors with biological activity against Spodoptera frugiperda

The development of new, more selective, environmental-friendly insecticide alternatives is in high demand for the control of Spodoptera frugiperda (S. frugiperda). The major objective of this work was to search for new potential S. frugiperda acetylcholinesterase (AChE) inhibitors. A ligand-based virtual screening was initially carried out considering six scaffolds derived from eugenol and the ZINC15, PubChem, and MolPort databases. Subsequently, molecular docking analysis of the selected compounds on the active site and a second region (determined by blind molecular docking) of the AChE of S. frugiperda was performed. Molecular dynamics and Molecular Mechanics Poisson–Boltzmann Surface Area analyses were also applied to improve the docking results. Finally, three new eugenol analogs were evaluated in vitro against S. frugiperda larvae. The virtual screening identified 1609 compounds from the chemical libraries. Control compounds were selected from the interaction fingerprint by molecular docking. Only three new eugenol analogs (1, 3, and 4) were stable at 50 ns by molecular dynamics. Compounds 1 and 4 had the best biological activity by diet (LC50 = 0.042 mg/mL) and by topical route (LC50 = 0.027 mg/mL), respectively. At least three new eugenol derivatives possessed good-to-excellent insecticidal activity against S. frugiperda

In silico evaluation of phenothiazine derivatives as trypanothione reductase inhibitors

Background: American trypanosomiasis is caused by parasite Trypanosoma cruzi, and it is considered a worldwide health problem. Current treatment consists of benznidazole and nifurtimox, which are not fully effective against both disease stages and have adverse effects. There is thus a need to find parasite-specific alternative treatments. Search of specific inhibitors of parasite-exclusive crucial enzymes is a known strategy. Trypanothione reductase (TR) enzyme is central in parasite’s redox system both for detoxification of reactive oxygen and nitrogen species as well as amino acid and nucleotide biosynthesis. Phenothiazine scaffold is known by pharmacologists as a very versatile structure and its derivatives have shown TR inhibition. A virtual screening of phenothiazine derivatives from PubChem database may permit finding potential TR inhibitors. Methodology: TR crystal was obtained from the PDB database (1GXF). A total of 100 phenothiazine derivatives complying with Lipinski’s rules were docked in TR active site using AutoDock Vina 1.1.2. Binding energy and interaction profiles, determined with PLIP (Protein-Ligand Interaction Profiler) server, were used to discriminate among derivatives. Results: Binding energy was found to be in the range of -10.9 to -6.1 kcal/mol compared to -8.8 kcal/mol of natural ligand trypanothione disulfide (TS2). Forty-two compounds showed a binding energy greater than or equal to natural ligand, top ten were determined interactions. Main interactions were found with residues important to TS2 binding: Phe396, Leu399, His461, Glu466 and Glu467. Conclusion: Best ranked compounds both by binding energy and interactions may be proposed as TR inhibitors and assayed in vitro to test effectivity