Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-kB Pathways

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF- B and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 M. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic dru

Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB

[EN] Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggabilitySIFinancial support came from Spanish MINECO (CTQ2015-68175-R, AGL2016-79813-C2-1-R, AGL2016-79813-C2-2-R and SAF2017-83575-R), ISCIII-RICET Network (RD12/0018/0002) and Consejería de Educación de la Junta de Castilla y León (LE020P17) co-financed by the Fondo Social Europeo of the European Union (FEDER-EU). P. G. J. acknowledges funding by Fundación Salamanca Ciudad de Cultura y Saberes (’‘Programme for attracting scientific talent to Salamanca’‘

Actividad analgésica y antiinflamatoria de derivados de podofilotoxina

La podofilotoxina es un producto natural inhibidor de la polimerización de la tubulina, que ha servido de prototipo para el desarrollo de distintos agentes antitumorales, actualmente en uso clínico como etopósido, tenipósido y etopophos. Reumacon, otro derivado semisintético similar a los anteriores, llegó a fase clínica para el tratamiento de la artritis reumatoide. Durante un estudio fitoquímico llevado a cabo sobre las hojas de Juniperus thurifera L., se aislaron, entre otros productos, varios ciclolignanos, podofilotoxina, desoxipodofilotoxina, desoxipicropodofilina y ácido thuriférico. Estos compuestos, obtenidos posteriormente mediante semisíntesis, fueron ensayados como analgésicos y antiinflamatorios. Desoxipodofilotoxina, una sustancia conformacionalmente rígida debido a la trans-lactona tensionada, muestra una elevada citotoxicidad; su epímero en C-8’, desoxipicropodofilina, con una cis-lactona más flexible y cien veces menos citotóxica, muestra un potente efecto analgésico, aunque menor actividad antiinflamatoria

New oxidized ent-kaurane and ent-norkaurane derivatives from kaurenoic acid

New oxidized ent-kaurane and ent-norkaurane derivatives were synthezised starting from kaurenoic acid. The spectroscopic characterization of all compounds is reported

Novel compound shows in vivo anthelmintic activity in gerbils and sheep infected by Haemonchus contortus

[EN] The control of gastrointestinal nematodes in livestock is becoming increasingly difficult due to the limited number of available drugs and the rapid development of anthelmintic resistance. Therefore, it is imperative to develop new anthelmintics that are effective against nematodes. Under this context, we tested the potential toxicity of three compounds in mice and their potential anthelmintic efficacy in Mongolian gerbils infected with Haemonchus contortus. The compounds were selected from previous in vitro experiments: two diamine (AAD-1 and AAD-2) and one benzimidazole (2aBZ) derivatives. 2aBZ was also selected to test its efficacy in sheep. In Mongolian gerbils, the benzimidazole reduced the percentage of pre-adults present in the stomach of gerbils by 95% at a dose of 200 mg/kg. In sheep, there was a 99% reduction in the number of eggs shed in faeces after 7 days at a dose of 120 mg/kg and a 95% reduction in the number of worm adults present in the abomasum. In conclusion, 2aBZ could be considered a promising candidate for the treatment of helminth infections in small ruminantsSIFinancial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and MICINN/AEI (PID2020- 119035RB-100). EVG was funded by FPU17/00627, FPU17/05346; VCGA, MAB, MCP and LGP are recipients of Junta de Castilla y León (JCyL) (LE082-18, LE051-18, LE135-19, LE096-20, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y competitividad; MMV, RYC-2015-18368

The Triterpenoid Betulin Protects against the Neuromuscular Effects ofBothrops jararacussuSnake VenomIn Vivo

[EN] We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND) preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA) preparation. Venom caused complete, irreversible blockade in PND (40 g/mL), but only partial blockade (∼30%) in EPSTA (3.6 mg/kg, i.m.) after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA) attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ∼70% in both preparations). Preincubation of venom with betulin (200 g/mL) markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom) virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite

3-Phenylcoumarins as Inhibitors of HIV-1 Replication

We have synthesized fourteen 3-phenylcoumarin derivatives and evaluated their anti-HIV activity. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as reporter. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Six compounds displayed NF-κB inhibition, four resulted Tat antagonists and three of them showed both activities. Three compounds inhibited HIV replication with IC50 values < 25 μM. The antiviral effect of the 4-hydroxycoumarin derivative 19 correlates with its specific inhibition of Tat functions, while compound 8, 3-(2-chlorophenyl)coumarin, seems to act through a mechanism unrelated to the molecular targets considered in this research

Personality Traits of an Entrepreneur, Determinants of Successful Microenterprise in Ireland

Why do certain individuals become entrepreneur and are successful, whereas others do not? The researchers in the entrepreneurship field attempt to answer that question by studying the personality traits of entrepreneurs for decades. Many confirm that the personality traits have a positive correlation with entrepreneurial intention and performance. Various studies suggest that the main entrepreneurial characteristics are risk attitudes, need for achievement, internal locus of control, innovativeness, and self-efficacy. However, debate exist if the personality traits are born or inherited and if the entrepreneurs’ actions are influenced by factors such as family, culture, education and market conditions. Although these aspects will be reviewed the focus of this study is on entrepreneurs’ personality traits only. Consequently, the aim of this study is to identify which of the personality traits, and whether there are traits, that are associated with operating successful microenterprise, from a perspective of an owner-manager of an established business in Ireland. The findings of this research revealed that the participants perceive themselves as individuals who possess indirectly four out of five most cited traits in the literature, which are need for achievement, locus of control, innovativeness and self-efficacy. In addition, they mentioned ability to relate to others, being organized and perform a quality work as the most important characteristics of a successful business owner. Also, other factors of environment influenced the participants’ decision to become an entrepreneur and Ireland was perceived as an attractive country to set up a business. Still, most of the participants do not perceive themselves as a successful entrepreneur. In summary, the inconclusiveness of this study generate more questions than it provide answers, coupled with this study limitations it is suggested that additional and more extensive research is desired

EducaFarma 11.0

Memoria ID2022-036. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2022-2023