Advances in Cysteine Protease B Inhibitors for Leishmaniasis Treatment.

The expression and release of cysteine proteases by Leishmania spp. and their virulence factors significantly influence the modulation of host immune responses and metabolism, rendering cysteine proteases intriguing targets for drug development. This review article explores the substantial role of cysteine protease B (CPB) in medicinal chemistry from 2001 to 2024, particularly concerning combatting Leishmania parasites. We delve into contemporary advancements and potential prospects associated with targeting cysteine proteases for therapeutic interventions against leishmaniasis, emphasizing drug discovery in this context. Computational analysis using the pkCSM tool assessed the physicochemical properties of compounds, providing valuable insights into their molecular characteristics and drug-like potential, enriching our understanding of the pharmacological profiles, and aiding rational inhibitor design. Our investigation highlights that while nonpeptidic compounds constitute the majority (69.2%, 36 compounds) of the dataset, peptidomimetic- based derivatives (30.8%, 16 compounds) also hold promise in medicinal chemistry. Evaluating the most promising compounds based on dissociation constant (Ki) and half maximal inhibitory concentration (IC50) values revealed notable potency, with 41.7% and 80.0% of nonpeptidic compounds exhibiting values < 1 µM, respectively. On the other hand, all peptidic compounds evaluated for Ki (43.8%) and IC50 (31.3%) obtained values < 1 µM, respectively. Further analysis identified specific compounds within both categories (nonpeptidic: 1, 2, and 4; peptidic: 48-52) as particularly promising, warranting deeper investigation into their structure-activity relationships. These findings underscore the diverse landscape of inhibitors in medicinal chemistry and highlight the potential of both nonpeptidic and peptide-based compounds as valuable assets in therapeutic development against leishmaniasis.

Synergistic Enhancement of 5-Fluorouracil Chemotherapeutic Efficacy by Taurine in Colon Cancer Rat Model.

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential ß-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/ß-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine.

In vitro and In vivo Activity of a New N-Oxide Derivative for Acne Vulgaris Treatment.

INTRODUCTION: Furoxan and benzofuroxan are compounds containing an N-oxide function, known for their diverse pharmacological properties, including antimicrobial and antiinflammatory effects. This study aimed to investigate these activities using an in-house library of N-oxide compounds. METHOD: Twenty compounds were tested against both Gram-positive and Gram-negative bacteria, including Cutibacterium acnes (C. acnes), a microorganism implicated in the development of acne vulgaris. One compound, (E)-4-(3-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3- (phenylsulfonyl)-1,2,5-oxadiazol-2-N-oxide (compound 15), exhibited selective antimicrobial activity against C. acnes, with a Minimum Inhibitory Concentration (MIC) value of 2 µg/mL. Indirect measurement of Nitric Oxide (NO) release showed that compound 15 and isosorbide dinitrate, when treated with L-cysteine, produced nitrite levels of 20.1% and 9.95%, respectively. Using a NO scavenger (PTIO) in combination with compound 15 in a culture of C. acnes resulted in reduced antimicrobial activity, indicating that NO release is part of its mechanism of action. Cytotoxicity assessments using murine macrophages showed cellular viability above 70% at concentrations up to 0.78 µg/mL. RESULTS: Measurements of Interleukin-1 beta (IL1-ß) and Tumor Necrosis Factor-alpha (TNF-α) indicated that compound 15 did not reduce the levels of these pro-inflammatory cytokines. Sustained NO production by inducible Nitric Oxide Synthase (iNOS) in macrophages or neutrophils has been found to be involved in the inflammatory process in acne vulgaris and lead to toxicity in surrounding tissues. Nitrite levels in the supernatant of murine macrophages were found to be decreased at a concentration of 0.78 µg/mL of compound 15, indicating an anti-inflammatory effect. In vivo studies were conducted using Balb/c nude mice inoculated subcutaneously with C. acnes. Cream and gel formulations of compound 15 were applied to treat the animals, along with commercially available anti-acne drugs, for 14 days. Animals treated with a cream base containing 5% of compound 15 exhibited less acanthosis with mild inflammatory infiltration compared to other groups, highlighting its anti-inflammatory properties. CONCLUSION: Similar results were observed in the benzoyl peroxide group, demonstrating that compound 15 presented comparable anti-inflammatory activity to the FDA-approved drug. These promising results suggest that compound 15 has a dual mechanism of action, with selective antimicrobial activity against C. acnes and notable anti-inflammatory properties, making it a potential prototype for developing new treatments for acne vulgaris.

BacPROTACs targeting Clp protease: a promising strategy for anti-mycobacterial drug discovery.

Tuberculosis (TB) has claimed more lives over the course of two millennia than any other infectious disease worldwide. In 2021, the World Health Organization (WHO) estimated that 10.6 million people were diagnosed with TB, resulting in the deaths of 1.4 million HIV-negative individuals. The emergence of multidrug-resistant TB (MDR-TB), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), and extensively drug-resistant TB (XDR-TB), poses the primary challenge to overcome in the coming years. We have recently conducted an extensive analysis of investments and research endeavours in the field, with the overarching objective of achieving the established milestone of TB eradication by the year 2030. Over the past several years, there has been notable progress in advancing a multitude of promising compounds, each possessing distinct mechanisms of action, into clinical phases of development. However, it is worth noting that strains of mycobacteria resistant to current antitubercular drugs have already emerged for some of these compounds The exploration of the innovative Proteolytic Target Chimeras (PROTACs) protein degradation approach has emerged as a viable avenue for the discovery of novel antimicrobials. While the ubiquitin system is exclusive to eukaryotic cells, certain bacteria use a similar degradation system that relies on the recognition of phosphorylated arginine residues (pArg) by the ClpC:ClpP (ClpCP) protease, thereby leading to protein degradation. In this opinion article, we have described and analized the advances in the use of PROTACs that leverage bacterial proteolytic machinery (BacPROTACs) to design new antitubercular agents. Scope Statement. The development of novel pharmaceuticals for tuberculosis treatment is deemed urgently necessary due to the emergence of resistant strains. In this context, the introduction of new technologies capable of alleviating the disease and attaining the objectives outlined by the World Health Organization is imperative. Among the innovative strategies, the degradation of proteins that are crucial for the survival of the bacillus holds promise for generating new medications, particularly those that are effective at treating latent (non-replicating) Mycobacterium tuberculosis. Within this perspective, we present the advancements and obstacles encountered in the exploration of new BacPROTAC compounds, with the intention of encouraging research and illuminating challenges associated with the implementation of BacPROTACs to address to the global tuberculosis crisis.

Chitosan surface modification modulates the mucoadhesive, permeation and anti-angiogenic properties of gellan gum/bevacizumab nanoparticles.

Bevacizumab (BVZ) was the first monoclonal antibody approved by the FDA and has shown an essential advance in the antitumor therapy of colorectal cancer (CRC), however, the systemic action of BVZ administered intravenously can trigger several adverse effects. The working hypothesis of the study was to promote the modulation of the mucoadhesion properties and permeability of the BVZ through the formation of nanoparticles (NPs) with gellan gum (GG) with subsequent surface modification with chitosan (CS). NPs comprising BVZ and GG were synthesized through polyelectrolyte complexation, yielding spherical nanosized particles with an average diameter of 264.0 ± 2.75 nm and 314.0 ± 0.01 nm, polydispersity index of 0.182 ± 0.01 e 0.288 ± 0.01, and encapsulation efficiency of 29.36 ± 0.67 e 60.35 ± 0.27 mV, for NPs without (NP_BVZ) and with surface modification (NP_BVZ + CS). The results showed a good ability of nanoparticles with surface modification to modulate the NPs biological properties.

Hydroxymethylnitrofurazone lymphatic uptake with nanostructured lipid carrier after oral administration in rats.

Background: Leishmaniasis, caused by the protozoan Leishmania sp., infects phagocyte cells present in lymphatic organs. This study demonstrates the influence of nanostructured lipid carrier-loaded hydroxymethylnitrofurazone (NLC-NFOH) on lymphatic uptake using a chylomicron-blocking flow model in rats. Method: Lymphatic uptake of NFOH was assessed 1 h after oral administration of dimethyl sulfoxide with NFOH or NLC-NFOH with and without cycloheximide pretreatment. Result: Dimethyl sulfoxide with NFOH and NLC-NFOH showed NFOH serum concentrations of 0.0316 and 0.0291 µg/ml, respectively. After chylomicron blocking, NFOH was not detected. Conclusion: Despite log P below 5, NFOH was successfully taken up by the lymphatic system. Long-chain fatty acids and particle size might be main factors in these findings. NLC-NFOH is a promising and convenient platform for treating leishmaniasis via oral administration.

The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors.

Antiretroviral Therapy (ART) is an effective treatment for human immunodeficiency virus (HIV) which has transformed the highly lethal disease, acquired immunodeficiency syndrome (AIDS), into a chronic and manageable condition. However, better methods need to be developed for enhancing patient access and adherence to therapy and for improving treatment in the long term to reduce adverse effects. From the perspective of drug discovery, one promising strategy is the development of anti-HIV prodrugs. This approach aims to enhance the efficacy and safety of treatment, promoting the development of more appropriate and convenient systems for patients. In this review, we discussed the use of the prodrug approach for HIV antiviral agents and emphasized nucleoside reverse transcriptase inhibitors. We comprehensively described various strategies that are used to enhance factors such as water solubility, bioavailability, pharmacokinetic parameters, permeability across biological membranes, chemical stability, drug delivery to specific sites/organs, and tolerability. These strategies might help researchers conduct better studies in this field. We also reported successful examples from the primary therapeutic classes while discussing the advantages and limitations. In this review, we highlighted the key trends in the application of the prodrug approach for treating HIV/AIDS.

Discovery of Novel Inhibitors of Cruzain Cysteine Protease of Trypanosoma cruz.

Chagas disease (CD) is a parasitic disease endemic in several developing countries. According to the World Health Organization, approximately 6-8 million people worldwide are inflicted by CD. The scarcity of new drugs, mainly for the chronic phase, is the main reason for treatment limitation in CD. Therefore, there is an urgent need to discover new targets for which new therapeutical agents could be developed. Cruzain cysteine protease (CCP) is a promising alternative because this enzyme exhibits pleiotropic effects by acting as a virulence factor, modulating host immune cells, and interacting with host cells. This systematic review was conducted to discover new compounds that act as cruzain inhibitors, and their effects in vitro were studied through enzymatic assays and molecular docking. Additionally, the advances and perspectives of these inhibitors are discussed. These findings are expected to contribute to medicinal chemistry in view of the design of new, safe, and efficacious inhibitors against Trypanosoma cruzi CCP detected in the last decade (2013-2022) to provide scaffolds for further optimization, aiming toward the discovery of new drugs.

Oxazolidinones as versatile scaffolds in medicinal chemistry.

Oxazolidinone is a five-member heterocyclic ring with several biological applications in medicinal chemistry. Among the three possible isomers, 2-oxazolidinone is the most investigated in drug discovery. Linezolid was pioneered as the first approved drug containing an oxazolidinone ring as the pharmacophore group. Numerous analogues have been developed since its arrival on the market in 2000. Some have succeeded in reaching the advanced stages of clinical studies. However, most oxazolidinone derivatives reported in recent decades have not reached the initial stages of drug development, despite their promising pharmacological applications in a variety of therapeutic areas, including antibacterial, antituberculosis, anticancer, anti-inflammatory, neurologic, and metabolic diseases, among other areas. Therefore, this review article aims to compile the efforts of medicinal chemists who have explored this scaffold over the past decades and highlight the potential of the class for medicinal chemistry.

Resveratrol and Curcumin for Chagas Disease Treatment-A Systematic Review.

Chagas disease (CD) is a neglected protozoan infection caused by Trypanosoma cruzi, which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage-characterized mainly by cardiac (i.e., cardiomyopathy) and digestive manifestations (i.e., megaesophagus, megacolon). Due to the involvement of the immuno-inflammatory pathways in the disease's progress, compounds exhibiting antioxidant and anti-inflammatory activity seem to be effective for controlling some clinical manifestations, mainly in the chronic phase. Resveratrol (RVT) and curcumin (CUR) are natural compounds with potent antioxidant and anti-inflammatory properties and their cardioprotective effect have been proposed to have benefits to treat CD. Such effects could decrease or block the progression of the disease's severity. The purpose of this systematic review is to analyze the effectiveness of RVT and CUR in animal and clinical research for the treatment of CD. The study was performed according to PRISMA guidelines and it was registered on PROSPERO (CDR42021293495). The results did not find any clinical study, and the animal research was analyzed according to the SYRCLES risk of bias tools and ARRIVE 2.0 guidelines. We found 9 eligible reports in this study. We also discuss the potential RVT and CUR derivatives for the treatment of CD as well.

Recent advancement in drug development of nitro(NO2 )-heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis.

Tuberculosis (TB) is an infectious disease caused predominantly by Mycobacterium tuberculosis (Mtb). It was responsible for approximately 1.4 million deaths worldwide in 2019. The lack of new drugs to treat drug-resistant strains is a principal factor for the slow rise in TB infections. Our aim is to aid the development of new TB treatments by describing improvements (last decade, 2011-2021) to nitro(NO2 )-based compounds that have shown activity or pharmacological properties (e.g., anti-proliferative, anti-kinetoplastid) against Mtb. For all compounds, we have included final correlations of minimum inhibitory concentrations against Mtb (H37 Rv).

An overview of sulfonamide-based conjugates: Recent advances for tuberculosis treatment.

In 2019, tuberculosis (TB) caused approximately 1.4 million deaths around the world. TB is an infectious respiratory disease mainly caused by Mycobacterium tuberculosis. The lack of new drugs to treat drug-resistant strains is a principal factor for the continuous slow rise in TB infections. Sulfonamides are active moieties in various drugs used against several sicknesses, including TB. Our aim is to aid the development of new TB treatments and drugs by describing recent improvements (2011-2021) to sulfonamide-based compounds.

Insight into Recent Drug Discoveries against Trypanosomatids and Plasmodium spp Parasites: New Metal-based Compounds.

Scaffolds of metal-based compounds can act as pharmacophore groups in several ligands to treat various diseases, including tropical infectious diseases (TID). In this review article, we investigate the contribution of these moieties to medicinal inorganic chemistry in the last seven years against TID, including American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT, sleeping sickness), leishmania, and malaria. The most potent metal-based complexes are displayed and highlighted in figures, tables and graphics; according to their pharmacological activities (IC50 > 10µM) against Trypanosomatids and Plasmodium spp parasites. We highlight the current progresses and viewpoints of these metal-based complexes, with a specific focus on drug discovery.

Recent Trends in Drug Development for the Treatment of Adenocarcinoma Breast Cancer: Thiazole, Triazole, and Thiosemicarbazone Analogues as Efficient Scaffolds.

Thiazoles, triazoles, and thiosemicarbazones function as efficient scaffolds in compounds for the treatment of several illnesses, including cancers. In this review article, we have demonstrated various studies involving these three pharmacophore classes (thiazoles, triazoles, and thiosemicarbazones) in medicinal chemistry over the last decade (2011-2021) with a focus on MCF-7 adenocarcinoma breast cancer cells. Our objective is to facilitate drug discovery of novel chemotherapeutic agents by detailing anti-proliferative compounds.

Hydroxymethylnitrofurazone (NFOH) decreases parasitaemia, parasitism and tissue lesion caused by infection with the Bolivia Trypanosoma cruzi type I strain in Swiss and C57BL/6 mice

Abstract The chemical hydroxymethylation of the antimicrobial nitrofurazone leads to the prodrug NFOH, also increases the anti-T. cruzi activities (in vitro and in vivo), as well as showed non-genotoxic (Ames and micronucleus assays). In the present study, we assessed the anti-T. cruzi effect of the NFOH In vivo - in acute Swiss and C57Bl/6 experimental Chagas models. The treatment started at 5 days post-infection during 20 consecutive days (orally, once day, 150mg/kg), and the parasitaemia as well as histopathology analysis were performed. In both experimental murine models, NFOH was able to reduce parasitemia blood avoiding parasitic reactivation, during immunosuppression period (dexamethasone 5mg/kg, 14 days), in 100% of the mice, and decrease tissue parasite nests, demonstrating absence of amastigote forms in all organs (100%) analyzed, data similar to benznidazole (BZN). Therefore, the results shown here pointing to the NFOH as promising compound for further preclinical studies, being a high potential drug to effective and safe chemotherapy to Chagas disease.

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi.

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.

Recent advances in drug discovery against Mycobacterium tuberculosis: Metal-based complexes.

Metal-based drugs are privileged motifs that act as primary pharmacophores in bioactive compounds for various diseases, including tuberculosis (TB). This potentially life-threatening and extremely contagious infectious disease is caused by Mycobacterium tuberculosis (Mtb). In 2018, TB infected about 10 million people and caused 1.2 million deaths worldwide. A large number of ligands are promising scaffolds in drug design, including heterocyclic, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates and miscellaneous. Moreover, several metal-based complexes have been studied for the treatment of numerous illnesses, including infectious diseases. To contribute to drug design, we identified the metal-based organometallic complexes against Mtb. Thus, in this review article, we analysed the recent contributions of metal-based scaffolds for design of new anti-Mtb drugs in the last decade (2011-2020). Besides, metal-based approaches will be presented in order to find out new antitubercular agents.

Thiazole, thio and semicarbazone derivatives against tropical infective diseases: Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria.

Thiazole, thiosemicarbazone and semicarbazone moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. In this review article, we critically analyzed the contribution of these scaffolds to medicinal chemistry in the last five years, focusing on tropical infectious diseases, such as Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria. We also present perspectives for their use in drug design in order to contribute to the development of new drugs.

Current advances in drug discovery for Chagas disease.

Chagas disease, also known as American trypanosomiasis, is one of the 17 neglected tropical diseases (NTDs) according to World Health Organization. It is estimated that 8-10 million people are infected worldwide, mainly in Latin America. Chagas disease is caused by the parasite Trypanosoma cruzi and is characterized by two phases: acute and chronic. The current therapy for Chagas disease is limited to drugs such as nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease. In addition, several side effects ranging from hypersensitivity to bone marrow depression and peripheral polyneuropathy have been associated with these drugs. Therefore, the current challenge is to find new effective and safe drugs against this NTD. The aim of this review is to describe the advances in the medicinal chemistry of new anti-chagasic compounds reported in the literature in the last five years. We report promising prototypes for drug discovery identified through target-based and phenotype-based strategies and present some important targets for the development of new synthetic compounds.

Promising nanotherapy in treating leishmaniasis.

Leishmaniases are infectious diseases caused by an intracellular protozoan in humans by 20 different species of Leishmania among more than 53 species. There are at least twelve million cases of infections worldwide and three hundred and fifty million people are at risk in at least 98 developing countries in Africa, South-East Asia, and the Americas. Only Brazil presented high burden for both visceral leishmaniasis (VL) and cutaneous (CL). Chemotherapy is the main means of dealing with this infection. Nevertheless, only a few effective drugs are available, and each has a particular disadvantage; toxicity and long-term regimens compromise most chemotherapeutic options, which decreases patient compliance and adherence to the treatment and consequently the emergence of drug-resistant strains. Nano drug delivery systems (NanoDDS) can direct antileishmanial drug substances for intracellular localization in macrophage-rich organs such as bone marrow, liver, and spleen. This strategy can improve the therapeutic efficacy and reduce the toxic effects of several antileishmanial drug substances. This review is an effort to comprehensively compile recent findings, with the aim of advancing understanding of the importance of nanotechnology for treating leishmaniases.