Editorial: Discovery and Development of Drugs for Neglected Diseases: Chagas Disease, Human African Trypanosomiasis, and Leishmaniasis

Twenty tropical diseases have been listed by the World Health Organization (WHO) as Neglected Tropical Diseases (NTDs). These tropical diseases are called “neglected” for three primary reasons: 1) These diseases are widespread worldwide among the economically weaker (neglected?) section of the society; 2) Although the total number of mortality, morbidity, disability, and health disparity caused annually by the NTDs is more than that attributed by the so-called elite diseases like cancer, diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), cardio- or neurological diseases but NTD patients do not receive comparable attention or treatment opportunities either from the governments or healthcare professionals or non-governmental organizations (NGOs); 3) The scope of drug development research in this field is minimal due to insufficient (negligible) funding, and pharma giants are not interested in developing effective drugs for NTDs on time, due to insignificant profit. It is highly challenging to develop new and novel drugs to combat these tropical diseases to upthrust the lifespan and lifestyle of the socioeconomically deprived people affected by NTDs (Figure 1). The major goal of this research topic is to shed light on the global scenario (current status of the ailments, treatment options, and recent drug development efforts) of three major NTDs, viz. Chagas disease (American trypanosomiasis), Human African trypanosomiasis (HAT), and Leishmaniasis. This research topic contains three reviews and seven research articles

Solución de dos estudios de caso bajo el uso de tecnología CISCO

En este primer escenario vamos identificar y a desarrollar simulaciones de conectividad básica en una red local, mediante la configuración inicial de dispositivos y terminales. Con su respectivo control de seguridad para el acceso al router y los switches, el tipo de cableado que se utilizara, su configuración de direccionamiento IPv4 y configuración de redes LAN, a través de la simulación de escenarios gracias a la herramienta Cisco Pack Trace, nos ayudara a interpretar la comunicación de datos mediante pruebas que ayudaran a validar su perfecta función. En el segundo escenario también se realizara una configuración de dispositivos de una red pequeña. Donde se manejara la configuración de un router y se Creara rutas predeterminadas para IPv4 e IPv6 que dirijan el tráfico a la interfaz Loopback 0, se configuraran dos switches y dos equipos que admitan tanto la conectividad IPv4 también donde se Cree un grupo DHCP para VLAN, como IPv6 para los hosts soportados. El router y los switches también deben administrarse de forma segura. Configurará el enrutamiento entre VLAN, DHCP, Etherchannel y port-security. Palabras clave: Loopback, Etherchannel, Dhcp, Enrutamiento, port-security, Redes.In this first scenario we are going to identify and develop simulations of basic connectivity in a local network, through the initial configuration of devices and terminals. With its respective security control for access to the router and switches, the type of cabling to be used, its IPv4 addressing configuration and LAN network configuration, through the simulation of scenarios thanks to the Cisco Pack Trace tool, we It will help to interpret the communication of data through tests that will help to validate its perfect function. In the second scenario, a configuration of devices of a small network will also be carried out. Where the configuration of a router will be handled and default routes will be created for IPv4 and IPv6 that direct the traffic to the Loopback 0 interface, two switches and two devices that support both IPv4 connectivity will also be configured where a DHCP group for VLANs will be created, as IPv6 for supported hosts. The router and switches must also be managed securely. You will configure routing between VLANs, DHCP, Etherchannel, and port-security. Keywords: Loopback, Etherchannel, Dhcp, Routing, port-security, Networks

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

An Expeditious Synthesis of 3-Amino B-Lactams Derived From Polyaromatic Compounds

A simple an effective method for the synthesis of a few trans 3-amino B-lactams derived from polyaromatic compounds has been accomplished via the deprotection of phthalimido groups with ethylene diamine

Stereochemical Preference Toward Oncotarget: Design Synthesis and in Vitro Anticancer Evaluation of Diastereomeric B-Lactams

Purpose: In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. Experimental Design: A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Results: Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam—β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis-3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Conclusions: Stereochemical preferences of the cis-β-lactams over their trans-counterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro

Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric &#x3B2;-lactams

ABSTRACT Purpose: In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. Experimental Design: A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Results: Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam—β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Conclusions: Stereochemical preferences of the cis-β-lactams over their transcounterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitr

The bioactivity of plant extracts against representative bacterial pathogens of the lower respiratory tract

<p>Abstract</p> <p>Background</p> <p>Lower respiratory tract infections are a major cause of illness and death. Such infections are common in intensive care units (ICU) and their lethality persists despite advances in diagnosis, treatment and prevention. In Mexico, some plants are used in traditional medicine to treat respiratory diseases or ailments such as cough, bronchitis, tuberculosis and other infections. Medical knowledge derived from traditional societies has motivated searches for new bioactive molecules derived from plants that show potent activity against bacterial pathogens. Therefore, the aim of this study was to evaluate the effect of hexanic, chloroformic (CLO), methanolic (MET) and aqueous extracts from various plants used in Mexican traditional medicine on various microorganisms associated with respiratory disease.</p> <p>Methods</p> <p>thirty-five extracts prepared from nine plants used in Mexican traditional medicine for the treatment of respiratory infections were evaluated against 15 control bacterial species and clinical isolates.</p> <p>Results</p> <p>Both chloroformic (CLO) and methanolic (MET) extracts of <it>Larrea tridentata </it>were active against Methicillin-resistant <it>S. aureus</it>, <it>B. subtilis </it>and <it>L. monocytogenes</it>. A MET extract of <it>L. tridentata </it>was also active against <it>S. aureus</it>, <it>S. pneumoniae</it>, <it>S. maltophilia</it>, <it>E. faecalis </it>and <it>H. influenzae </it>and the CLO extract was active against <it>A. baumannii</it>. An Aqueous extract of <it>M. acumitata </it>and a MET extract of <it>N. officinale </it>were active against <it>S. pneumoniae</it>. CLO and MET extracts of <it>L. tridentata </it>were active against clinical isolates of <it>S. aureus</it>, <it>S. pneumoniae </it>and <it>E. faecalis</it>.</p> <p>Conclusion</p> <p>Overall, our results support the potential use of <it>L. tridentata </it>as a source of antibacterial compounds.</p

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