Multi-target Compounds against Trypanosomatid Parasites and Mycobacterium tuberculosis.

Multi-target drug treatment has become popular as a substitute for traditional monotherapy. Monotherapy can lead to resistance and side effects. Multi-target drug discovery is gaining importance as data on bioactivity becomes more abundant. The design of multi-target drugs is expected to be an important development in the pharmaceutical industry in the near future. This review presents multi-target compounds against trypanosomatid parasites (Trypanosoma cruzi, T. brucei, and Leishmania sp.) and tuberculosis (Mycobacterium tuberculosis), which mainly affect populations in socioeconomically unfavorable conditions. The article analyzes the studies, including their chemical structures, viral strains, and molecular docking studies, when available. The objective of this review is to establish a foundation for designing new multi-target inhibitors for these diseases.

Inhibitors Targeting Hepatitis C Virus (HCV) Entry.

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system's activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.

Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis.

Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, and in silico ADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5-20 mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood-brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10 mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light-dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20 mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10 mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10 mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.

Strategies in Medicinal Chemistry to Discover New Hit Compounds against Ebola Virus: Challenges and Perspectives in Drug Discovery.

Ebola Virus (EBOV) is an infectious disease that mainly affects the cardiovascular system. It belongs to the Filoviridae family, consisting of filamentous envelopes and non-segmented negative RNA genome. EBOV was initially identified in Sudan and Zaire (now named the Democratic Republic of Congo) around 1967. It is transmitted mainly by contact with secretions (blood, sweat, saliva, and tears) from infected wild animals, such as non-human primates and bats. It has gained more prominence in recent years due to the recent EBOV outbreaks that occurred from 2013 to 2016, resulting in approximately 28,000 infected individuals, with a mortality rate of 40- 70%, affecting mainly Liberia, Guinea, and Sierra Leone. Despite these alarming levels, there is still no FDA-approved drug for the effective treatment of these diseases. The most advanced drug to treat EBOV is remdesivir. However, it is a high-cost drug and is available only for intravenous use. In this sense, more investments are needed in the research focused on the development of new antiviral drugs. In this context, medicinal chemistry strategies have been improving and increasingly discovering new hits that can be used in the future as a treatment against these diseases. Thus, this review will address the main advances in medicinal chemistry, such as drug discovery through computational techniques (virtual screening and virtual high throughput screening), drug repurposing, phenotypic screening assays, and employing classical medicinal chemistry, such as bioisosterism, metabolism-based drug design, and the discovery of new inhibitors through natural products, thereby presenting several promising compounds that may contain the advance of these pathogens.

Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents.

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.

Druggable targets from coronaviruses for designing new antiviral drugs.

Severe respiratory infections were highlighted in the SARS-CoV outbreak in 2002, as well as MERS-CoV, in 2012. Recently, the novel CoV (COVID-19) has led to severe respiratory damage to humans and deaths in Asia, Europe, and Americas, which allowed the WHO to declare the pandemic state. Notwithstanding all impacts caused by Coronaviruses, it is evident that the development of new antiviral agents is an unmet need. In this review, we provide a complete compilation of all potential antiviral agents targeting macromolecular structures from these Coronaviruses (Coronaviridae), providing a medicinal chemistry viewpoint that could be useful for designing new therapeutic agents.