TITLE: To Identify And Optimize The Activity Of A Compound Against The Trypanosoma Cruzi, For Studying The Particular Level Of Infection In A Mouse Model For The Chagas Disease And Improve Drug Discovery.
The abstract addresses the descriptive analysis about the Chagas disease as well as its protozoan parasite Trypanosoma cruzi. The study addresses its distribution across the world although it presents a vague aspect in terms of migration factors responsible for the chronic infection in severely infected patients. But the abstract lacks a major aspect of treatment for Chagas disease. The presentstudy addresses the methodology relevant tohit compound optimization after the screening of phenotypic library in comparison to Trypanosoma cruzi (Harrison et al., 2020). But it did not address as to how thelevel of optimization was achieved. It lacked major aspects in terms of the methodology compound being used as well as the software being used. In addition to this, the study lacked as to why there was a need for optimization in the treatment of chronic illness.
To identify the optimized structure of the T. Cruzi, causative compound for analyzing the stage of activity of Chagas infection and analyze new drug targets.
INTRODUCTION AND BACKGROUND:
The study authors have addressed the background about the causative agent of the Chagas which is Trypanosoma cruzialong with its major distribution. The study background addresses majoraspects of the disease cycle as well as its level of infection and mode transmission. It provides a biological background about the microorganism as well as its mode of causing the disease. But a major aspect of the present studies of drug discovery and potential targets for the drug are missing. It lacks major aspects of the present treatment options and how the structure of the infecting molecules looks and its categorization. There is a major need to identify major drug targets as well as the advanced options for the treatment via non-pharmacological options. It lacks the major treatment options for chronic disease patterns although it provides a majorexplanation for the acute Chagas disease (Wall et al., 2020). The efficiency of various medicines such as benznidazolewas analyzed and it presented a detailed view about the acute Chagas ailment treatment options.Various other medications were also included such as benznidazole along with nifurtimox which reported potential side but the literature review majorly lacked a descriptive review about the objective of the optimising compound.
The methodology clearly presented a chemistry concept which improved the relevance of the method along with a descriptive review of the materials used. The general procedure was described in a stepwise manner for compound A which was N-[3-(2-cyclohex-1-enyl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-6-yl]-acetamide. It is observed that choice of the compound was clearly highlighted by its use as the potential target. The method starts with a diagrammatic representation for the synthesis of compounds. It begins with the Synthesis of 5-Acetamide-R1 – Substituted Quinazolinediones by utilizing the Ethyl Chloroformate.
The first step is the addition of N-(2,4-Dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)- acetamide to Triphosgene along with 5-acetamido-2-amino-benzoic-acid and the 1,4-dioxane and then heating at 110 °C for a time period of 6 hours along with drying.
The second step was the addition of 5-Acetamido-2-amino-N-(2-(cyclohex-1-en-1-yl)ethyl)- benzamide. Then the addition of DMAP to cyclohexenyl ethylamine.
Then it was followed by the Synthesis of 5-Acetamide-R1 – Substituted Quinazolinediones via utilizing the Carbonyldiimidazole. N-(2,4-Dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)acetamide .
It involves the step of reduction via amination followed by debenzylation. Then the subsequent step is the amidations via the 5-Acetamido-2-aminobenzoic acid as well as relevant amine.
Then it was followed by the preparation of 6-Aminopyrido[2,3-d]- pyrimidine-2,4(1H,3H)-diones.
The final step is the acetylation process for compound of 6-Aminopyrido[2,3-d]- pyrimidine-2,4(1H,3H)-dione. Thus the procedure is quite descriptive and highly easy to replicate by other researchers. The methods provide a detailed review of the compounds and the chemicals being added at various temperatures. After the synthesis was followed by activity against T. Cruzi. Then it involves In Vitro Cytotoxicity by using the L-6 Cell. The next step is Nephelometry for aqueous Solubility. The next step is the Intrinsic Clearance along with Pharmacokinetics In Vivo studies. The pharmacodynamics methods can be used in adherencewith pharmacokinetics for improving the efficacy of study results (De Rycker et al., 2018). Also, the methods must involve bioinformatics assays for designing the drug target. Also, it must involve metagenomic libraries for screening.
The control compound which was utilized was the benznidazole relevant to the T. cruzi assay. It involved various variables such as EC50 as well as the use of podophyllotoxin. the reliability of study results was further enhanced as the cytotoxicity assay utilized the clogP by utilizing the StarDrop and compared against the L6 to deprioritize compounds.
After optimization for use in treating the compound which was acetamide derivative was measured having an EC90 value of 38 ng/mL. It was analyzed that this compound has to be used two times every day at a dose of 30 mg/kg via oral route and it was analyzed that the Ctrough free concentration was analyzed at EC50.
This dose must be utilized specifically for a period of ten days in the sample species suffering from Chagas disease as it is the first line of action for treatment in acute disease cases. This will majorly increase the success rate and probability. Thus the optimum compound number 43 had EC50 value for T. cruzi is 0.026 μM along with L6 cells EC50 value of 3.8 μM). In addition to this, the kinetic aqueous solubilitywas 73 μMalong with mouse Cli value of 3.2 mL/min/g and the mouse PPB value of 0.028 Fu. Furthermore, it was analyzed that figures, as well as tables, lack any proper legends. Also, it is significant to note that the legends donot have enough explanation about the various compounds in terms of a common name (Lidani et al., 2019). There is a need foran explanation of the compounds used and their origin along with their direct impact on chronic disease treatment.
The variable utilized in the experiment provided significant results about the significant activity concerning the hit compound number one in association with its closely related analogues which was analyzed to be limited to the analogues. The study results clearly showed that there was a logical connection of the reason forthe conduct of experiments in terms of determining the treatment via dosing the population for approximately 10 days (Menna-Barreto et al., 2019). Thus the chemical compound clearly showed a major decrease in parasite levels in comparison to the control compound after dosing with PO. But the author has majorly missed how the optimized compound has an increased efficacy in terms of treatment of chronic conditionsBut the authors were critical of the results in terms of the requirement for increased optimization in relevance to solubility as well as selectivity in terms of future treatment options. The authors were critical in terms of limitation in dosing due to solubility as well as the optimum concentration of dose which was closely related tothe highest level of tolerated dose (Thomas et al., 2018). Yes, they were open-minded to other options for chronic disease treatment in terms of investigating the compounds with more analogues by investigating better models for comparing posaconazole-like as well as benznidazole-like compounds.
The study clearly focuses on improving the level of evidence for in-vivo proof for the optimized compoundin terms of efficacy in the infection model. There is a need for increased efficiency and research to focus on the increasedselectivity as well as solubility in relevance to dosing. There must be advanced study for the development of improved infection models in relevance to translational pathways related with Chagas ailment and include a diverse variety of compounds in the context of their improved success rate of kill assays along with activity agonist various strains causing infection.
De Rycker, M., Baragaña, B., Duce, S.L. and Gilbert, I.H., 2018.Challenges and recent progress in drug discovery for tropical diseases. Nature, 559(7715), pp.498-506.
Harrison, J.R., Sarkar, S., Hampton, S., Riley, J., Stojanovski, L., Sahlberg, C., Appelqvist, P., Erath, J., Mathan, V., Rodriguez, A. and Kaiser, M., 2020.Discovery and optimization of a compound series active against Trypanosoma cruzi, the causative agent of Chagas disease. Journal of medicinal chemistry, 63(6), pp.3066-3089.
Lidani, K.C.F., Andrade, F.A., Bavia, L., Damasceno, F.S., Beltrame, M.H., Messias-Reason, I.J. and Sandri, T.L., 2019. Chagas disease: from discovery to a worldwide health problem. Frontiers in public health, 7, p.166.
Menna-Barreto, R.F.S., 2019. Cell death pathways in pathogenic trypanosomatids: lessons of (over) kill. Cell Death Dis 10 (2): 93.
Thomas, M.G., De Rycker, M., Torrejon, I.C., Thomas, J., Riley, J., Spinks, D., Read, K.D., Miles, T.J., Gilbert, I.H. and Wyatt, P.G., 2018.2, 4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease. Bioorganic & medicinal chemistry letters, 28(18), pp.3025-3030.
Wall, R.J., Carvalho, S., Milne, R., Bueren-Calabuig, J.A., Moniz, S., Cantizani-Perez, J., MacLean, L., Kessler, A., Cotillo, I., Sastry, L. and Manthri, S., 2020. The Qi site of cytochrome b is a promiscuous drug target in Trypanosomacruzi and Leishmaniadonovani. ACS infectious diseases, 6(3), pp.515-528.