Current Topics in Medicinal Chemistry - Volume 21, Issue 21, 2021

Neglected tropical diseases (NTDs) are a group of approximately 20 diseases that affect part of the population in Sub- and Tropical countries. In the past, pharmaceutical industries and governmental agencies have invested in the control, elimination and eradication of such diseases. Among these diseases, Chagas disease (CD) and Human African trypanosomiasis (HAT) are a public health problem, mainly in the countries from the American continent and sub-Saharan African. In this context, the search for new therapeutic alternatives against such diseases has been growing in recent years, presenting cysteine proteases as the main strategy to discover new anti-trypanosomal drugs. Thus, cruzain and rhodesain enzymes are targets widely studied, since the cruzain is present in all stages of the parasite's life, related to the stages of proliferation and differentiation and infection of macrophages; while the rhodesain is related to the immune defense process. In addition, knowledge about the amino acid sequences and availability of X-ray complexes have stimulated the drug searching against these targets, mainly through molecular modeling studies. Thus, this review manuscript will be addressed to cruzain and rhodesain inhibitors developed in the last 10 years, which could provide basis for new lead compounds in the discovery of new trypanocidal drugs. We found 117 studies involving inhibitors of cruzain and rhodesain, being thiosemicarbazones, semicarbazones, N-acylhydrazones, thiazoles-hydrazone, thiazolidinones-hydrazones, oxadiazoles, triazoles, triazines, imidazoles, peptidomimetic, and others. All references were obtained using “cruzain” or “rhodesain” and “inhibitor” as keywords in Science Direct, Bentham Science, PubMed, Espacenet, Springer, ACS Publisher, Wiley, Taylor and Francis, and MDPI (Multidisciplinary Digital Publishing Institute) databases. Finally, we highlighted all these chemical classes of molecules to provide valuable information that could be used to design new inhibitors against Chagas disease and sleeping sickness in the future.

Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 μM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.

Tuberculosis is an infectious disease engulfing millions of lives worldwide; it is caused by mammalian Tubercle bacilli, Mycobacterium tuberculosis complex, which may consist of strains viz. M. tuberculosis hominis (human strain), M. microti, M. pinnipedii and M. canettii. The other pathogenic strain is M. africanum, which belongs to the M. tuberculosis complex and it is fully virulent for humans. The non-pathogenic strains in the complex may include M. fortuitum and M.smegmatis. Extensive research has been carried out to combat this dangerous disease. World Health Organization proposed Directly Observed Treatment Short-course regimen (DOTS) for the eradication of TB. In addition, the compounds such as TBA-7371, TBI-166, AZD5847 and PBTZ-169 are under clinical trials whereas the recently FDA-approved anti-tubercular drugs are Pretomanid (PA-824), Bedaquiline (TMC207), Linezolid (PNU-100480) and Delamanid (OPC-67683). The early detection of mycobacterium tuberculosis can be permanently cured by DOTS comprising Pyrazinamide (Z), Isoniazid (H), Rifampin (R) and Ethambutol (E). The duration of treatment depends on the viability of the disease. DOTS can target to disrupt the biosynthesis of mycobacterial cell wall proteins expressed by various genes. Overexpression of these genes may produce drug-resistant due to dose misuse or the intake of quality compromised anti-tubercular drug regimen. Therefore, in the present review, there has been a necessity to report the second line anti-tubercular chemotherapeutics to target various proteins which are the building blocks of M. tb cell wall, overexpression of which may produce drug resistance.

Background: Neglected diseases require special attention when looking for new therapeutic alternatives, as these are diseases of extreme complexity and severity that affect populations belonging to lower social classes who lack access to basic rights, such as sanitation. Introduction: Among the alternatives available for obtaining new drugs is Medicinal Chemistry, which is responsible for the discovery, identification, invention, and preparation of prototypes. In this perspective, the present work aims to make a bibliographic review on the recent studies of Medicinal Chemistry applied to neglected diseases. Methods: A literature review was carried out by searching the “Web of Sciences” database, including recent articles published on the Neglected Drug Design. Results: In general, it was noticed that the most studied neglected diseases corresponded to Chagas disease and leishmaniasis, with studies on organic synthesis, optimization of structures, and molecular hybrids being the most used strategies. It is also worth mentioning the growing number of computationally developed studies, providing speed and optimization of costs in the procurement process. Conclusion: The CADD approach and organic synthesis studies, when applied in the area of Medicinal Chemistry, have proven to be important in the research and discovery of drugs for Neglected Diseases, both in terms of planning the experimental methodology used to obtain it and in the selection of compounds with higher activity potential.