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![Paul Ehrlich (1854–1915) and Sahachiro Hata (1873–1938), Frankfurt 1910. Their partnership led to the discovery of arsphenamine (reprinted courtesy of the Paul-Ehrlich-Institut, Langen, Germany) [10] .](profile/Felix-Bosch-2/publication/23148318/figure/fig1/AS:277550635995139@1443184636733/Paul-Ehrlich-1854-1915-and-Sahachiro-Hata-1873-1938-Frankfurt-1910-Their.png)
Paul Ehrlich (1854–1915) and Sahachiro Hata (1873–1938), Frankfurt 1910. Their partnership led to the discovery of arsphenamine (reprinted courtesy of the Paul-Ehrlich-Institut, Langen, Germany) [10] .
Source publication
On the centenary of Paul Ehrlich's Nobel Prize, this German researcher deserves to be remembered as a pioneer in a large number of scientific disciplines. As a result of his enthusiasm and scientific abilities, dedication, and contacts with other scientists of his time, he was able to make countless contributions in fields as diverse as histology,...
Contexts in source publication
Context 1
... Ehrlich ( fig. 1 ) and the Russian im- munologist Ilya Mechnikov , who discovered phagocytosis, received the Nobel Prize for Physiology or Medicine in 1908 [1] . On the centenary of this event, it is fitting to commemorate Paul Ehrlich's life and work not only because of this distinction, but also because of his many other contributions, particularly ...
Context 2
... agent of syphilis, a disease whose impact on society was comparable to that of AIDS today. Given the similarity between spirochetes and try- panosomes, Hoffmann suggested that Ehrlich use arsen- ical compounds to treat patients with syphilis. Upon the arrival at the laboratory of his Japanese student and col- league Sahachiro Hata (1873-1938) ( fig. 1 ; table 1 ), who had been able to infect rabbits with syphilis, Ehrlich asked him to reassess all arsenicals synthesized until then. When he tested compound No. 606, Hata observed that it had truly notable curative properties against syphilis. Ehrlich had just discovered the magic bullet he had so intently been seeking: arsphenamine. ...
Citations
... Previously, sodium arsenite was used as an inhibitor of Trypanosomiasis. With years of modification, melarsen form of Atoxyl-Melarsoprol was developed [57]. Melarsoprol is a trivalent form of melarsen oxide. ...
Synthetic drugs currently prescribed for the treatment of Human African Trypanosomiasis (HAT) are non-specific, toxic, demand extended therapeutic regimes and are of varying efficacy. Along with the challenging demographic and socio-economic hurdles, the everincreasing risk of drug resistance is another major problem to be addressed. Cysteine protease, Heat shock proteins (HSP-90), Trypanothione reductase (TR), Farnesyl diphosphate synthase, Glucose-6-phosphate dehydrogenase, UP-4-galactose epimerase, and Cytidine triphosphate synthetase are potential enzymatic targets for the development of novel inhibitors against HAT which are the main focus of this review. The potential enzymatic targets of Trypanosoma brucei, especially small molecules like cysteine proteases and heat shock proteins are identified as major candidates for the sustenance of the parasite, their proliferation, infection, and spread of the disease. The development of new compounds to combat the disease by thorough ligand modification has been explored in the current review. Extracting these compounds and studying their efficacy, toxicity, and target mechanism extensively, this review has proposed a list of different compounds, including some synthetic and natural compounds along with multi-target inhibitors such as acoziborole, fexinidazole, etc. Potential inhibitors against these enzymatic targets of the T. brucei are important candidates for designing novel therapeutics against HAT. Multi-target inhibitors have also been identified as crucial molecules because of their potential advantage against the development of drug resistance.
Method
The potential enzymatic targets of Trypanosoma brucei, especially small molecules like cysteine proteases and heat shock proteins are identified as major candidates for the sustenance of the parasite, their proliferation, infection and spread of the disease. Development of new compounds to combat the disease by thorough ligand modification have been explored in the current review.
Result
Extracting these compounds and studying their efficacy, toxicity, and target mechanism extensively, this review have proposed a list of different compounds, including some synthetic and natural compounds along with multi-target inhibitors such as acoziborole, fexinidazole etc.
... Recorte do periódico Pharol (Juiz de Fora, MG), de 01 de dezembro de 1910, anunciando o Salvarsan 50 Anúncio do Salvarsan no periódico A Província (Recife, PE), em 01 de janeiro de 1911 51 Quadro 1. Estruturas químicas de alguns compostos organoarsênicos que participaram da história da terapêutica da sífilis Atoxyl Salvarsan (composto 606) (estrutura inicialmente adotada por Ehrlich e sua equipe que perdurou durante o século XX) Estrutura do Salvarsan atualmente aceita (mistura de trímeros e pentâmeros de arsênio com ligações simples) Neosalvarsan (composto 914) Fonte: Adaptado de Bosch e Rosich (2008).43 ...
... Em 1905, após conhecer a publicação do pesquisador canadense da Escola de Medicina Tropical de Liverpool HaroldThomas (1875Thomas ( -1931, da atividade antitripanossômica do ácido (4-aminofenil)arsônico, substância conhecida como Atoxyl − por ser menos tóxica do que os compostos arsenicais inorgânicos − promoveu, com o químico orgânico alemão Alfred Bertheim, centenas de modificações estruturais na molécula do organoarsênico, a fim de encontrar a sua sonhada "bala mágica", que fosse nociva aos agentes infecciosos sem gerar efeitos colaterais.42 Até então, o tratamento das tripanossomoses com o Atoxyl exigia altas doses da substância, acarretando recorrentes casos de cegueira.43 Segundo Benchimol, 44 o médico Harold Thomas, responsável por divulgar a ação do Atoxyl contra os tripanossomos, publicou os trabalhos finais a esse respeito quando já estava no Brasil, enviado em 1905 para Manaus no intuito de estudar a febre amarela. ...
CHEMISTRY AND SYPHILIS: A HISTORICAL JOURNEY. The relationship between syphilis and chemistry is remarkable due to its being the first example in western history of a comprehensive attempt by researchers from many countries and cultures to direct their efforts to tackle a serious health problem by means of chemical science. This effort started to take place at the time when the science of chemistry was already beginning to emerge, apart from alchemy. Thus, the fight against syphilis was closely linked to the emergence of iatrochemistry, or medicinal chemistry, which eventually gave rise, centuries later, to chemotherapy. Many of the early iatrochemical compounds in the XVIth century were of mineral origin, and often also synthetic. One of the pioneers of this trend was Paracelsus, who occupies a prominent place in the process. Along the centuries a number of different chemical approaches were attempted to cure syphilis until the advent of antibiotics in the mid-twentieth century, after so much time in which syphilis remained a physical and moral scourge of humankind, challenging all those that endeavoured to find its cure. In this article we recount many fascinating aspects of the application of chemistry in this quest, showing its development in the world as well as in Brazil, throughout its entire history.
... 18 In 1872-1874, medical student Paul Ehrlich, who studied selective tissue staining, first put forward a hypothesis about the existence of chemoreceptors. 19 According to his hypothesis, chemoreceptors were special tissue structures that specifically interacted with chemical substances. Ehrlich considered this interaction as a possibility for various diseases therapy. ...
... 20 In 1907, Ehrlich's significant discovery was the drug Salvarsan (diphenamine arsenide) -a remedy for syphilis and trypanosomosis, much more effective and less toxic than inorganic mercury preparations that were used before. 19 Following Salvarsan's invention, the development of chemotherapy began, which involved the need to modify the structures of potential drugs for the most effective effect on the affected organ. 21 Ehrlich's receptor theory together with the concept of chemotherapy became the starting point of modern medical chemistry. ...
A crucial direction in the progress of modern medical chemistry is the development and improvement of theoretical investigation methods of drugs mechanisms of action, predicting their activity, and virtual design of new drugs. This review describes the history of targeted search for biologically active compounds, current in silico approaches and tools used in the rational design of potential drugs, in particular the main computational strategies used in modern drug design are presented and outlines the main methodologies for implementing these strategies.
... The spectrum of the ligand showed broad bands centered at 3450 and 3373 cm -1 which assigned to υ(OH). However, strong broad bands appeared in the 3600-3320 and 3380-2670 cm -1 ranges confirmed the presence of non-equivalent intra and intermolecular hydrogen bondings [14][15][16][17][18]. Also, the spectrum of the ligand displayed tow bands at 1700 and 1650cm -1 assignable to υ(C=O) and υ(C=N) respectively [19][20][21][22] . Medium bands were observed at 1540, 1450, 818 and 750 cm -1 which are related to vibration of ν(Ar) ring. ...
New binary Cu(II), Mn(II), Ag(I), Fe(III), Co(II), Ni(II), Zn(II) ,Cd(II), Mg(II), Al(III) and Ca(II) metal complexes derived from (Z)-N'-(2-hydroxybenzylidene)-2-((Z)-(2-hydroxybenzylidene)amino)pro p-anehydrazide ligand were prepared. Physicochemical studies (IR, UV-Vis, Mass, 1H-NMR, Magnetism , DTA and TGA, conductivity and ESR) were carried out. The measurements revealed that, the ligand coordinated to the metal ion in a neutral hexadentate or dibasic hexadentate mode through nitrogen atoms of imino group and oxygen atom of the hydroxyl group in protonated or non-protonated form. All metal complexes are non-electrolytic in nature as suggested by molar conductance measurements. The complexes are adopted to be tetragonal distorted octahedral geometry around the metal ions. The cytotoxic activity of the ligand as well as some of its metal complexes was evaluated against breast cancer (MCF-7). It is worth noting, the cytotoxic activity was enhanced upon complexation. Also, it was interestingly found that, Zn(II) complex (7) recorded the highest IC50 value against MCF-7. However, the other tested complexes showed a weak cytotoxicity against the same cell line compared with a standard drug (vinblastine sulfate).The molecular docking of the tested. INDRODUCTION Complexes was carried out to know the number of bonding and the energy with the breast gene. Amides and their derivatives constitute a amount class of compounds in organic chemistry. These compounds have interesting biological properties such as anti-inflammatory, analgesic, anticonvulsant, antituberculous, antitumor, anti-HIV and antimicrobial activity [1]. Amides are important compounds for drug design, as possible ligands for metal complexes, organocatalysis and also for the syntheses of heterocyclic compounds [2]. The ease of preparation, increased hydrolytic stability relative to imines, and tendency toward crystallinity are all desirable characteristics of amides. Due to these positive traits, amides had been under study for a long time, but much of their basic chemistry remains unexplored. Amides ligands create an environment similar to the one present in biological systems usually by making coordination through oxygen and nitrogen atoms. Various important properties of carbonic acid amides, along with their applications in medicine and analytical chemistry, have led to increased interest in their complexation characteristics with transition metal ions [3]. The DOI
... Yet despite this no chemical agents were available to successfully treat bacterial infections. In the early nineteenhundreds however, things changed with the discovery of arsphenamine, an arsenic compound that when used with extreme care could cure the venereal disease, syphilis (Bosch and Rosich, 2008). Arsphenamine was sold under the trade name Salversan. ...
The recognition that microorganisms (germs) are the major cause of human disease, not surprisingly, eventually had a dramatic impact on medicine. Although there were some farsighted proponents of the germ theory during the late seventeen hundreds, until well into the mid-nineteenth century the theory that disease was caused by bad air (so-called Miasma) held sway. The recognition that microbes can cause disease led to major improvements in hygiene and eventually led to the introduction of antiseptic and then aseptic surgery. The development of penicillin and other antibiotics at last provided a means of controlling bacterial infection, allowing for the application complex medical procedures, such as open heart and transplant surgery. The appearance of antibiotic resistance is no threatening the so-called golden age of antibiotics and there is a desperate need to develop new antibiotics, or new approaches to disease control. This review aims to provide a broad account of the history of the germ theory, which highlights some common misconceptions about the work of some of the pioneers involved, and emphasises the neglected contribution of others.
... Back at the beginning of the last century, Paul Ehrlich, a pioneer of the magic bullet approach (die Zauberkugel) for the development of medicines, had shown that different dyes, often taken from the cloth dyeing industry, could bind to specific molecules in the cell, thus providing contrast and allowing different subcellular compartments to be distinguished. [8] Ehrlich looked to nature, observing; "antitoxins and antibacterial substances are, so to speak, charmed bullets which strike only those objects for whose destruction they are produced by the organism." [9] Since then, perhaps as foreseen by Ehrlich, medicines have moved from small chemical molecules to the newer biologics, which include biopolymers, proteins, nucleic acid and even cells. ...
The FDA modernization act 2.0, signed into law by President Biden in December 2022 encourages the use of alternatives to animal testing for drug discovery. Cell-based assays are one important alternative, however they are currently not fit for purpose. The use of 3D, tissue engineered models represents a key development opportunity, to enable development of models of human tissues and organs. However, much remains to be done in terms of understanding the materials, both bioderived and synthetic that can be incorporated into the models, to provide structural support and also functional readouts. This perspective provides an overview on the history of drug safety testing, with a brief history on the origins of the Food and Drug Administration (FDA). It then goes on to discuss the current status of drug testing, outlining some of the limitations of animal models. In vitro , cell-based models are discussed as an alternative for some parts of the drug discovery process, with a brief foray into the beginnings of tissue culture and a comparison of 2D vs 3D cell culture. Finally, this perspective lays out the argument for implementing tissue engineering methods into in vitro models for drug discovery and safety testing.
Graphical abstract
Drug safety testing is a long and expensive process. Advanced, tissue engineered (human) models such as organ-on-chip and spheroids or organoids, are higher throughput methods that can be used to complement, or sometimes replace, animal models currently used. Made with biorender.com
... Chemotherapy has a long history that dates back to the early 20th century, but its use to treat cancer was started in the 1930s. The word "chemotherapy" was created by the German scientist Paul Ehrlich to refer to the use of chemicals to cure the disease [28]. Ehrlich had a keen interest in alkylating agents. ...
The limitations associated with the conventional treatment of cancer have necessitated the design and development of novel drug delivery systems based mainly on nanotechnology. These novel drug delivery systems include various kinds of nanoparticles, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, hydrogels, and polymeric micelles. Among the various kinds of novel drug delivery systems, chitosan-based nanoparticles have attracted the attention of researchers to treat cancer. Chitosan is a polycationic polymer generated from chitin with various characteristics such as biocompatibility, biodegradability, non-toxicity, and mucoadhesiveness, making it an ideal polymer to fabricate drug delivery systems. However, chitosan is poorly soluble in water and soluble in acidic aqueous solutions. Furthermore, owing to the presence of reactive amino groups, chitosan can be chemically modified to improve its physiochemical properties. Chitosan and its modified derivatives can be employed to fabricate nanoparticles, which are used most frequently in the pharmaceutical sector due to their possession of various characteristics such as nanosize, appropriate pharmacokinetic and pharmacodynamic properties, non-immunogenicity, improved stability, and improved drug loading capacity. Furthermore, it is capable of delivering nucleic acids, chemotherapeutic medicines, and bioactives using modified chitosan. Chitosan and its modified derivative-based nanoparticles can be targeted to specific cancer sites via active and passive mechanisms. Based on chitosan drug delivery systems, many anticancer drugs now have better effectiveness, potency, cytotoxicity, or biocompatibility. The characteristics of chitosan and its chemically tailored derivatives, as well as their use in cancer therapy, will be examined in this review.
... In the year 1909, Paul Enrich and Sahachiro Hata discovered "Salvarsan" -an organic compound of Arsenic, which could be used for treating Syphilis. 7,8 An inorganic compound of Arsenic -Arsenic trioxide, is currently allowed for treatment purposes in refractory acute promyelocytic leukemia. 9 The objective of the study is to evaluate Arsenic as a toxic and therapeutic agent through the ages and to do a comparative study based on different research publications on Arsenic. ...
Introduction: Arsenic is enormously toxic in chronic as well as in
acute manifestations and this fact has been established in different
works of literature. Arsenic gets inside the body by skin absorption,
ingestion, and inhalation, then dispersed into different organs.
Methodology: The objective of the study is to do a comparative
study based on different research publications on Arsenic toxicity
and its therapeutic uses. For retrieval of arsenic-related articles, the
Scopus database was used and the results were presented in form of
bibliometric tables. The articles which were published in the
duration of 14 years from January 2008 to October 2021 were taken
for this study. Total 7606 documents were retrieved from the
SCOPUS database in which 6330 documents supported therapeutic
nature and 1276 supporting toxic nature of Arsenic. Maximum
documents on therapeutic uses of Arsenic (9.54 %) are published in
the year 2020. Conclusion: Arsenic has been a source of constant
fascination and has influenced the human psyche since time
immemorial, owing to Arsenic’s ability to act both as a therapeutic
and toxic agent. A critical study of the publications on Arsenic can
open new vistas in Arsenic research.
... Further arsenoxides, [ 91,92] arsenobenzenes, and arsenophenols were developed by a reduction in atoxyl and inserting a hydroxyl group at the para position of the benzene ring. The melarsen form of atoxyl, melarsoprol, was then formed [101]. ...
Background:
Trypanosomiasis, caused by protozoan parasites of the Trypanosoma genus, remains a significant health burden in several regions of the world. Cysteine proteases play a crucial role in the pathogenesis of Trypanosoma parasites and have emerged as potential therapeutic targets for the development of novel antiparasitic drugs.
Introduction:
This review article aims to provide a comprehensive overview of the role of cysteine proteases in trypanosomiasis and their potential as therapeutic targets. We discuss the biological significance of cysteine proteases in Trypanosoma parasites and their involvement in essential processes, such as host immune evasion, cell invasion, and nutrient acquisition.
Methods:
A comprehensive literature search was conducted to identify relevant studies and research articles on the role of cysteine proteases and their inhibitors in trypanosomiasis. The selected studies were critically analyzed to extract key findings and provide a comprehensive overview of the topic.
Results:
Cysteine proteases, such as cruzipain, TbCatB and TbCatL, have been identified as promising therapeutic targets due to their essential roles in Trypanosoma pathogenesis. Several small molecule inhibitors and peptidomimetics have been developed to target these proteases and have shown promising activity in preclinical studies.
Conclusion:
Targeting cysteine proteases and their inhibitors holds great potential for the development of novel antiparasitic drugs against trypanosomiasis. The identification of potent and selective cysteine protease inhibitors could significantly contribute to the combat against trypanosomiasis and improve the prospects for the treatment of this neglected tropical disease.
... C, H, N and Cl analyses were determined at the Analytical Unit of Cairo University, Egypt. Standard gravimetric methods were used to determine metal ions [20][21][22] . All metal complexes were dried under vacuum over P 4 O 10 . ...
