Current Topics in Medicinal Chemistry - Volume 23, Issue 9, 2023

Tropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.

Trypanosomiasis is caused by parasitic protozoan trypanosomes in vertebrates. T. cruzi and T. brucei are causative agents of Chagas disease (CD) and Human African Trypanosomiasis (HAT), respectively. These life-threatening diseases are a serious threat to public health, with considerable incidence in sub-Saharan African and continental Latin America countries. Although WHO validated mitigated number of HAT cases in Togo (June 2020) and Cote d’Ivoire (December 2020), serious efforts need to be performed for the elimination of the disease. Antigenic variation of trypanosomal parasites provides a major bottleneck for developing effective vaccines. In the absence of human vaccines or chemoprophylaxis, the control of trypanosomatid infections may be envisaged through the eradication of vectors, management of animal reservoirs, and chemotherapy. A small number of chemical agents are currently available for antitrypanosomal treatments, and most of them are associated with toxicity, lack of efficacy, and non-oral route of administration. Given the restricted applicability of current medications, numerous efforts have been made for the synthesis and biological evaluation of heterocyclic scaffolds as antitrypanosomal candidates. In light of the above considerations, we were prompted to describe chemical diversity within privileged 5- membered heterocycles (imidazoles, thiazoles, triazoles and tetrazoles) as antitrypanosomal agents. The main purpose of the study was to throw light on the structure-activity relationship (SAR) of the relevant structures. To capture the recent structural diversity within reported cases, small molecules that belonged to the recent 7-year period (2015-2021) have been discussed. The available medications have also been briefly reviewed.

Malaria has been a major parasitic disease in tropical and subtropical regions and is estimated to kill between one and two million people (mainly children) every year. Novel anti-malarial agents are urgently needed to combat the malarial parasites enduring resistance to the current medications, leading to increased morbidity and mortality. The heterocycles, holding a prominent position in chemistry and found in both natural and synthetic sources, have shown several biological activities including anti-malarial activity. Towards this goal, several research groups have reported the design and development of novel and potential anti-malarial agents like artemisinin, benzimidazole, benzothiazole, chalcone, cyclopeptide, fosmidomycin, furan, indole oxadiazole, 2-oxindoles, peroxides, pyrazole, pyrazolines, pyridines, pyrimidine, pyrrolidine, quinazoline, quinazolinone, quinolone, quinoline, thiazole, triazole and other scaffolds acting against newly emerging anti-malarial targets. The present work reports the complete quinquennial coverage of anti-malarial agents reported during 2016-2020 with a view of providing the merits and demerits of reported anti-malarial scaffolds, structure-activity relationship, along with their in vitro/ in vivo/ in silico profiles to the medicinal chemists working in the field of design and discovery of novel anti-malarial agents.

Parasitic diseases affect millions of people and animals, predominantly in the tropics, including visitors to tropical countries and other areas. Efficient and low-cost treatments for infections caused by various parasites are not yet available. Antiparasitic drugs have some drawbacks, such as toxicity and the development of resistance by parasites. This has motivated many researchers to focus on the discovery of safe, effective and affordable antiparasitic drugs, both among drugs already available for other diseases and new compounds synthesized or isolated from natural sources. Furthermore, steroid and triterpenoid compounds attract the attention of pharmacologists, chemists and biochemists owing to their broad application in the treatment of various diseases. Isolation of steroid and triterpenoid compounds from natural sources with antiparasitic efficacy is an attractive choice for scientists. On the other hand, these compounds can be transformed into more potent forms by modifying the basic skeleton. This review presents a collection of isolated and synthesized steroid and triterpenoid compounds from 2018 to 2021 that have been reported to be effective against certain parasitic protozoa and helminths. A total of 258 compounds have been identified with antimalarial, antitrypanosomal, antileishmanial, anti-Toxoplasma, and/or anthelmintic activity. The described investigations of antiparasitic compounds may be helpful for further drug development.

Nitroaromatic compounds have been used for treating parasitic diseases since the 1960s. Pharmacological alternatives to treat them are under observation. However, for the most neglected diseases, such as those caused by worms and less known protozoans, nitro compounds are still among the drugs of choice, despite their well-known collateral effects. In this review, we describe the chemistry and the uses of the still most employed nitroaromatic compounds for treating parasitosis caused by worms or lesser-known protozoans. We also describe their application as veterinary drugs. The most accepted mechanism of action seems to be the same, leading to collateral effects. For this reason, a special session was dedicated to discussing toxicity, carcinogenicity, and mutagenesis, as well as the most acceptable aspects of the known structure-activity/toxicity relationships involving nitroaromatic compounds. It employed the SciFindern search tool from the American Chemical Society in the search for the most relevant bibliography within the field, exploring keyword expressions such as “NITRO COMPOUNDS” and “BIOLOGICAL ACTIVITY” (within Abstracts or Keywords) and concepts related to parasites, pharmacology and toxicology. The results were classified according to the chemical classes of nitro compounds, being the most relevant studies regarding journal impact and interest of the described results chosen to be discussed. From the found literature, it is easy to notice that nitro compounds, especially the nitroaromatic ones, are still widely used in antiparasitic therapy, despite their toxicity. They also are the best starting point in the search for new active compounds.