Vaccination against Trichinella spiralis: Potential, Limitations and Future Directions

Trichinellosis is a food-borne parasitic disease caused by round worms of the genus Trichinella. The majority of human outbreaks are attributed to consumption of raw or undercooked pork meat contaminated with T. spiralis muscle larvae. A blocking-transmission vaccine against trichinellosis will allow preventing swine infection and will contribute to disease control. In this chapter, different vaccine candidates so far developed against T. spiralis, including first-, second-, and third-generation vaccines, are discussed. Most vaccine candidates are based on a unique antigen mainly from the muscle larva stage, inducing with some exceptions, partial protection although a mix Th1/Th2 immune response is elicited. Therefore, the need for identification of new antigens from different parasite stages focusing on infective intestinal larvae, adult, and newborn larvae stages as well as the evaluation of their protective capacity in pigs is presented. The design of multi-epitope vaccines and the use of adjuvants or immunomodulatory molecules capable to polarize the immune response to a Th2-type-protective response are discussed as imperative elements of modern vaccines. Plant-based vaccines and probiotics as excellent tools for vaccine development against T. spiralis are also presented as an attractive platform for veterinary vaccines

Antiprotozoal and antimycobacterial activities of Persea americana seeds

BACKGROUND: Persea americana seeds are widely used in traditional Mexican medicine to treat rheumatism, asthma, infectious processes as well as diarrhea and dysentery caused by intestinal parasites. METHODS: The chloroformic and ethanolic extracts of P. americana seeds were prepared by maceration and their amoebicidal, giardicidal and trichomonicidal activity was evaluated. These extracts were also tested against Mycobacterium tuberculosis H37Rv, four mono-resistant and two multidrug resistant strains of M. tuberculosis as well as five non tuberculosis mycobacterium strains by MABA assay. RESULTS: The chloroformic and ethanolic extracts of P. americana seeds showed significant activity against E. histolytica, G. lamblia and T. vaginalis (IC(50) <0.634 μg/ml). The chloroformic extract inhibited the growth of M. tuberculosis H37Rv, M. tuberculosis MDR SIN 4 isolate, three M. tuberculosis H37Rv mono-resistant reference strains and four non tuberculosis mycobacteria (M. fortuitum, M. avium, M. smegmatis and M. absessus) showing MIC values ≤50 μg/ml. Contrariwise, the ethanolic extract affected only the growth of two mono-resistant strains of M. tuberculosis H37Rv and M. smegmatis (MIC ≤50 μg/ml). CONCLUSIONS: The CHCl(3) and EtOH seed extracts from P. americana showed amoebicidal and giardicidal activity. Importantly, the CHCl(3) extract inhibited the growth of a MDR M. tuberculosis isolate and three out of four mono-resistant reference strains of M. tuberculosis H37Rv, showing a MIC = 50 μg/ml. This extract was also active against the NTM strains, M. fortuitum, M. avium, M. smegmatis and M. abscessus, with MIC values <50 μg/ml

Design, Synthesis and Evaluation of 2,4- Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β- tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β- tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well- known tubulin- depolymerizing agents that have close binding sites in the β- tubulin. In this study, we designed and synthesized a set of nine 2,4- diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC- 3, HCT- 15, MCF- 7, MDA- MB- 231, and SK- LU- 1), a noncancerous one (COS- 7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4- e and 4- i on tubulin organization and polymerization was analyzed on the SK- LU- 1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4- i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non- N- substituted 2,4- diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.More is not always better: A set of nine 2,4- diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4- diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/3/cmdc202000185-sup-0001-misc_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/2/cmdc202000185_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/1/cmdc202000185.pd

Antiprotozoal and Antimycobacterial Activities of Pure Compounds from Aristolochia elegans Rhizomes

We analyzed the antimycobacterial activity of the hexane extract of rhizomes from Aristolochia elegans. Some compounds of this extract were purified and tested against a group of drug-resistant Mycobacterium tuberculosis strains. We also evaluated their antiprotozoal activities. The hexane extract was active against M. tuberculosis H37Rv at a MIC = 100 μg mL−1; the pure compounds eupomatenoid-1, fargesin, and (8R,8′R,9R)-cubebin were active against M. tuberculosis H37Rv (MIC = 50 μg mL−1), while fargesin presented activity against three monoresistant strains of M. tuberculosis H37Rv and a MDR clinical isolate of M. tuberculosis (MIC < 50 μg mL−1). Both the extract and eupomatenoid-1 were very active against E. histolytica and G. lamblia (IC50 < 0.624 μg mL−1); in contrast, fargesin and (8R,8′R,9R)-cubebin were moderately active (IC50 < 275 μg mL−1). In this context, two compounds responsible for the antimycobacterial presented by A. elegans are fargesin and cubebin, although others may exert this activity also. In addition to the antimycobacterial activity, the hexane extract has important activity against E. histolytica and G. lamblia, and eupomatenoid-1 is one of the compounds responsible for the antiparasite activity

Benzimidazole derivatives as new and selective inhibitors of arginase from leishmania mexicana with biological activity against promastigotes and amastigotes

17 pags, 6 figs, 3 tabs, 2 schs. -- Supplementary materials are available online at https://www.mdpi.com/article/10 .3390/ijms222413613/s1.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.This research was funded by the Consejo Nacional de Ciencia y Tecnología (CONACyT), grants 257848 (A.T.-V.) and 258694 (C.A.-D.). The work in Spain was funded by a grant from the Spanish Ministry of Science, Innovation and Competitiveness PID2020-115331GB-100 to J.A.-H.Peer reviewe

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β- tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β- tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well- known tubulin- depolymerizing agents that have close binding sites in the β- tubulin. In this study, we designed and synthesized a set of nine 2,4- diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC- 3, HCT- 15, MCF- 7, MDA- MB- 231, and SK- LU- 1), a noncancerous one (COS- 7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4- e and 4- i on tubulin organization and polymerization was analyzed on the SK- LU- 1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4- i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non- N- substituted 2,4- diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.More is not always better: A set of nine 2,4- diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4- diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/3/cmdc202000185-sup-0001-misc_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/2/cmdc202000185_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/1/cmdc202000185.pd

Insights into the structure and inhibition of <i>Giardia intestinalis</i> arginine deiminase: homology modeling, docking, and molecular dynamics studies

<p><i>Giardia intestinalis</i> arginine deiminase (<i>GiADI</i>) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes <i>GiADI</i> an attractive target for drug design against <i>G. intestinalis</i>. One approach in the design of inhibitors of <i>GiADI</i> could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of <i>GiADI</i> obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of <i>GiADI</i> identified through molecular dynamics simulation studies. An <i>in silico</i> analysis of druggability using the structure of <i>GiADI</i> was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential <i>GiADI</i> inhibitors were identified by docking of a set of 3196 commercial and 19 <i>in</i>-<i>house</i> benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand–enzyme complexes.</p

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR