Advances in the Medicinal Chemistry of Neglected Tropical Disease and Related Infectious Diseases

Neglected Tropical Diseases (NTDs) are a group of infectious diseases that affect thousands of people all over the world. These diseases mainly affect the population that lives in poverty and lack sanitation, prevalent mainly in tropical and subtropical countries. In this sense, they are called “neglected” due to the low investment in P&D in pharmaceutical companies' discovery and development of new agents. Thus, developing new drugs against these diseases is one of the two biggest challenges for academic researchers around the world, and increasingly, there is a need for advances in medicinal chemistry methods and the identification of molecular targets for the design of innovative drugs that can put an end to these threats. Finally, here we will present methods used in medicinal chemistry in recent years in the design of drugs against these agents, with a focus on the development of new compounds against Nmyristoyltransferase, nitroreductases, topoisomerases, pyrimidine synthesis pathway, and mitochondrial alterations constantly explored against various NTDs. We hope this chapter serves as a guide for researchers worldwide searching for innovative drugs that can finally help these people and improve the health of the world's population.

Over the last decades, neglected tropical diseases (NTDs), especially leishmaniasis, have been the focus of several drug discovery programs. The identification of the pathogen druggable targets and the ability to map the differences between parasites and human enzymes have contributed to the increased interest in the development of new lead compounds. Despite this progress, there remain substantial gaps with respect to developing efficient medications that can be the foundation for surmounting the acquired resistance and overcoming treatment failure. With this background in mind, this chapter will discuss the validated drug targets with a special focus on the reported structural determinants of activity of novel antileishmanial agents. The aim is to introduce an updated overview of the medicinal chemistry aspects of leishmaniasis to the scientific community. 

American trypanosomiasis, also known as Chagas Disease (CD), is a Neglected Tropical Disease (NTD) of the infectious type, having the protozoan parasite Trypanosoma cruzi (T. cruzi) as the etiologic agent. The CD is usually transmitted to human hosts by means of the Triatomine bug bites, and it is endemic in regions characterized by substandard environmental conditions, such as Central and South America. The globalization of goods and people significantly contributed to spreading CD to regions not previously affected and/or not adequate for the proliferation of transmitting bugs. This chapter reviews the main features of the disease, its main symptoms, the actual therapies, and the most advanced, although not for clinical use and currently considered for further development.

Also known as sleeping sickness, human African trypanosomiasis (HAT) is caused by protozoan parasites of the genus Trypanosoma transmitted between humans by the bites of tsetse flies (glossina). HAT is caused by two parasite subspecies - Trypanosoma brucei gambiense (accounting for 92% of reported cases and causes chronic illness) and Trypanosoma brucei rhodesiense (accounting for 8% of reported cases and is responsible for the acute form of the disease). The former can advance, affecting the central nervous system, while the latter can develop rapidly with multiple organs, including the brain, being invaded. If left untreated, HAT is generally fatal. According to the World Health Organization, in the period 2016 – 2020, about 55 million people were at risk of infection, with nearly 1000 cases reported in 2018. Current treatment options have limitations such as complex administration procedures, limited effectiveness, emergence of drug resistance, and undesirable side effects. Therefore, new drugs are required. In this book chapter, we summarize current efforts aimed at identifying new drug candidates and their corresponding mechanisms of action. We highlight medicinal chemistry optimization efforts for different candidates while giving detailed insights into the mechanism of function for the corresponding drug targets. Such information is of value as it equips drug discovery scientists with information about chemical modifications, which can lead to improvement in certain physicochemical and biological properties of new chemical entities.

Schistosomiasis, a neglected tropical disease, affects millions worldwide. Treatment and control strategies rely entirely on the single drug praziquantel (PZQ), making the prospect of resistance emergence worrisome. The pressing need to introduce new antischistosomal agents necessitates exploring and repurposing chemotherapeutic history besides designing novel leads. In this context, this chapter summarizes the parasite life cycle, its clinical manifestations, and the progress in schistosomiasis chemotherapy with an overview of the validated drug targets, the emergence of drug resistance, and vaccination trials.

Dengue is still a major concern as we are yet to identify a potent inhibitor, and unfortunately, there is loss of life associated with this disease; however, the fatalities are low, but every year, dengue is an added burden to the medical infrastructure. In a world hit by COVID-19 pandemic, dengue is yet another serious burden. To date, we do not have any approved medicine to combat this disease. Symptomatic treatment to reduce the fever and intensive care facilities for critical patients is the only treatment protocol adopted as of now. Earlier, it was a disease of tropical nations of the world, but now it has been observed that it has extended its reach beyond the tropical and subtropical nations. The WHO data suggest that the year 2023 saw a record over 5000 reported cases of death due to dengue in about 80 countries across the world. These data further call for the urgency in identifying inhibitors for dengue. In the book chapter, we have compiled the efforts made so far in the last decade to give a DENV inhibitor. Our extensive survey of the literature indicated that protease of DENV was the most explored target and besides these targets like NS5 methyltransferase, RdRp, and E proteins did report few molecules. The success of proteases for drug discovery in diseases like HIV and HCV has encouraged researchers to exploit the DENV proteases. In this book chapter, we identified varying scaffolds contributing to the inhibition of Dengue virus and by different mechanisms. 

Malaria continues to endanger over half of the world's population, claiming 1-2 million lives each year. The main causative agents are Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Both cause widespread mortality and morbidity, and they impose a significant socioeconomic burden, particularly in poor nations. The emergence and dissemination of resistance to currently available antimalarial medications have generated a crisis scenario among experts. Unfortunately, artemisinin-resistant parasitic strains have been observed in Southeast Asia. Several approaches that include, combination therapy, exploitation of natural products, drug resistance reversers, covalent bitherapy, identification of novel targets, and development of vaccines, have been explored to surmount the issue of drug resistance. In the absence of effective vaccinations, the disease has been mostly managed with chemotherapy and chemoprophylaxis. Over the past year, breakthroughs in technology such as molecular evolutionary and population genetic techniques have exposed the malaria parasite genome, considerably contributing to the understanding of the targets and dissemination of parasite treatment resistance. The rapid discovery and molecular characterization of novel targets have paved the path for the development of new antimalarial medicines. To find chemically varied, efficacious medications, new pharmacophores, and validated targets are necessary. Functional genomics and structure-based drug design can help in the search for novel potential targets and therapeutic candidates. Once the putative targets are validated, which are capable of providing effective and safe drugs, they can be used for screening compounds to discover new leads, which, successively, can be utilized in the lead optimization process. Combinatorial chemistry, along with as well as high throughput screening technologies, is used to generate huge numbers of structurally diverse compounds. This chapter discusses possible chemotherapeutic targets for antimalarial therapy and their locations inside the malaria parasite, as well as new lead compounds for rationally designing new antimalarial medicines.

The Zika virus (ZIKV) is responsible for the infection of millions of people, causing mild flu-like symptoms and even severe symptoms, which are related to the nervous system, including Guillain-Barré syndrome and microcephaly. Nonetheless, it still remains with no antiviral treatments or effective vaccine to prevent it. Thus, several efforts have been addressed to discover a medicinal alternative to disrupt the ZIKV infection worldwide. Notwithstanding these facts, this chapter will focus on the main antiviral targets associated with ZIKV and their inhibitors identified so far. In principle, viral and host factors related to the ZIKV life cycle could be targeted for the development of novel drugs. In fact, there are some macromolecular targets that could be further investigated aiming to develop anti-ZIKV drugs, some of which remain still a few explored. In summary, this chapter encourages the exploration of new opportunities for medicinal chemists to design novel anti-ZIKV agents, providing a solid hope for future treatments against this disease.

Tuberculosis (TB) is a highly contagious and potentially life-threatening infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). Despite significant progress in medical science, TB remains a global health concern, affecting millions of people worldwide. Efforts to combat this disease have led to the development of various treatment regimens, and research in TB drug discovery continues to be a crucial area of study. Identifying the new drug targets is essential in the fight against MDR TB, TDR TB, and XDR TB. Owing to the current situation, the key aspect of modern drug discovery is based on the concept of structural information along with functional activity relationships to combat tuberculosis disease. The structure-activity relationship (SAR) involves understanding the relationship between a compound's chemical structure and its biological activity. The line of treatment of MTB addresses multiple targets, such as various ribosomal targets, including the exit tunnel of the 50S subunit of ribosome, DNA gyrase (GyrB), Inosine-5’-monophosphate dehydrogenase (IMPD), Adenosine kinases (AK), Chorismate mutase (CM), and many other targets as well. This chapter provides a complete insight into the existing medications versus newly developed drug molecules based on SAR, their protein targets, modes of action, and mechanisms of resistance. By comprehending the intricate relationship between the chemical structure of drugs and their biological activity, it is possible to develop more effective therapies to combat this deadly disease.

Fascioliasis, caused by trematode parasites of the Fasciola spp. remains a significant global health concern, affecting both humans and livestock. This neglected tropical disease, along with other food-borne trematodes, impacts over 10% of the world's population, resulting in substantial economic losses exceeding $3 billion annually in the livestock industry. Since no vaccine has been developed so far, current disease control relies mainly on drugs, particularly triclabendazole, which although effective, faces challenges due to reported resistance in many regions. With Fasciola hepatica being the common fluke, its wide distribution and intricate life cycle, emphasize the importance of understanding parasite epidemiology and biology and addressing drug resistance. However, few efforts have been pursued in the last decade to develop new drugs against fascioliasis. There are different approaches to drug discovery. Screening methodologies may target essential parasite proteins through in silico or in vitro studies, employing protein docking and molecular dynamic simulations. This enables the rapid identification of potential drug candidates for subsequent in vitro or in vivo testing. Alternatively, phenotypic screenings with cultured parasites offer a broader understanding of drug efficacy but present challenges in terms of automation and the unknown mode of action of the drug candidates. Also, drug repurposing has emerged as a promising strategy in recent years. This approach accelerates the drug development process, addressing the lengthy timelines typically associated with bringing novel drugs to the market. This chapter provides a comprehensive overview of drug discovery efforts in the last ten years for fascioliasis treatment. In-depth discussions on drugs targeting specific F. hepatica molecular components are presented followed by phenotypic screenings with synthetic and natural compounds. The chapter concludes with a review of some scarce initiatives in drug repurposing, providing an overview of the various strategies employed to address drug discovery in fascioliasis.