Acridine derivatives have been found with anticancer and antinociceptive activities. Herein, we aimed to evaluate the toxicological, antitumor, and antinociceptive actions of ...N’-(6-chloro-2-methoxyacridin-9-yl)-2-cyanoacetohydrazide (ACS-AZ), a 9-aminoacridine derivative with antimalarial activity. The toxicity was assessed by acute toxicity and micronucleus tests in mice. The
in vivo
antitumor effect of ACS-AZ (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.) was determined using the Ehrlich tumor model, and toxicity. The antinociceptive efficacy of the compound (50 mg/kg, i.p.) was investigated using formalin and hot plate assays in mice. The role of the opioid system was also investigated. In the acute toxicity test, the LD
50
(lethal dose 50%) value was 500 mg/kg (i.p.), and no detectable genotoxic effect was observed. After a 7-day treatment, ACS-AZ significantly (
p
< 0.05) reduced tumor cell viability and peritumoral microvessels density, suggesting antiangiogenic action. In addition, ACS-AZ reduced (
p
< 0.05) IL-1β and CCL-2 levels, which may be related to the antiangiogenic effect, while increasing (
p
< 0.05) TNF-α and IL-4 levels, which are related to its direct cytotoxicity. ACS-AZ also decreased (
p
< 0.05) oxidative stress and nitric oxide (NO) levels, both of which are crucial mediators in cancer known for their angiogenic action. Moreover, weak toxicological effects were recorded after a 7-day treatment (biochemical, hematological, and histological parameters). Concerning antinociceptive activity, ACS-AZ was effective on hotplate and formalin (early and late phases) tests (
p
< 0.05), characteristic of analgesic agents with central action. Through pretreatment with the non-selective (naloxone) and μ1-selective (naloxonazine) opioid antagonists, we observed that the antinociceptive effect of ACS-AZ is mediated mainly by μ1-opioid receptors (
p
< 0.05). In conclusion, ACS-AZ has low toxicity and antitumoral activity related to cytotoxic and antiangiogenic actions that involve the modulation of reactive oxygen species, NO, and cytokine levels, in addition to antinociceptive properties involving the opioid system.
Colorectal cancer (CRC) is the third most common cancer globally, with high mortality. Metastatic CRC is incurable in most cases, and multiple drug therapy can increase patients' life expectancy by 2 ...to 3 years. Efforts are being made to understand the relationship between topoisomerase enzymes and colorectal cancer. Some studies have shown that higher expression of these enzymes is correlated to a poor prognosis for this type of cancer. One of the primary drugs used in the treatment of CRC is Irinotecan, which can be used in monotherapy or, more commonly, in therapeutic schemes such as FOLFIRI (Fluorouracil, Leucovorin, and Irinotecan) and CAPIRI (Capecitabine and Irinotecan). Like Camptothecin, Irinotecan and other compounds have a mechanism of action based on the formation of a ternary complex with topoisomerase I and DNA providing damage to it, therefore leading to cell death. Thus, this review focused on the principal works published in the last ten years that demonstrate a correlation between the inhibition of different isoforms of topoisomerase and
cytotoxic activity against CRC by natural products, semisynthetic and synthetic compounds of pyridine, quinoline, acridine, imidazoles, indoles, and metal complexes. The results revealed that natural compounds, semisynthetic and synthetic derivatives showed potential
cytotoxicity against several colon cancer cell lines, and this activity was often accompanied by the ability to inhibit both isoforms of topoisomerase (I and II), highlighting that these enzymes can be promising targets for the development of new chemotherapy against CRC. Pyridine analogs were considered the most promising for this study, while the evaluation of the real potential of natural products was limited by the lack of information in their work. Moreover, the complexes, although promising, presented as the main limitation the lack of selectivity.
Neglected tropical diseases (NTDs) are prevalent in tropical and subtropical countries, and schistosomiasis is among the most relevant diseases worldwide. In addition, one of the two biggest problems ...in developing drugs against this disease is related to drug resistance, which promotes the demand to develop new drug candidates for this purpose. Thus, one of the drug targets most explored,
Cathepsin B1 (SmCB1 or Sm31), provides new opportunities in drug development due to its essential functions for the parasite's survival. In this way, here, the latest developments in drug design studies targeting SmCB1 were approached, focusing on the most promising analogs of nitrile, vinyl sulphones, and peptidomimetics. Thus, it was shown that despite being a disease known since ancient times, it remains prevalent throughout the world, with high mortality rates. The therapeutic arsenal of antischistosomal drugs (ASD) consists only of praziquantel, which is widely used for this purpose and has several advantages, such as efficacy and safety. However, it has limitations, such as the impossibility of acting on the immature worm and exploring new targets to overcome these limitations. SmCB1 shows its potential as a cysteine protease with a catalytic triad consisting of Cys
, His
, and Asn
. Thus, design studies of new inhibitors focus on their catalytic mechanism for designing new analogs. In fact, nitrile and sulfonamide analogs show the most significant potential in drug development, showing that these chemical groups can be better exploited in drug discovery against schistosomiasis. We hope this manuscript guides the authors in searching for promising new antischistosomal drugs.
Neglected tropical diseases (NTDs) constitute a group of approximately 20 infectious diseases that mainly affect the impoverished population without basic sanitation in tropical countries. These ...diseases are responsible for many deaths worldwide, costing billions of dollars in public health investment to treat and control these infections. Among them are the diseases caused by protozoa of the Trypanosomatid family, which constitute Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness), and Leishmaniasis. In addition, there is a classification of other diseases, called the big three, AIDS, tuberculosis, and malaria, which are endemic in countries with tropical conditions. Despite the high mortality rates, there is still a gap in the treatment. The drugs have a high incidence of side effects and protozoan resistance, justifying the investment in developing new alternatives. In fact, the Target-Based Drug Design (TBDD) approach is responsible for identifying several promising compounds, and among the targets explored through this approach, N-myristoyltransferase (NMT) stands out. It is an enzyme related to the co-translational myristoylation of N-terminal glycine in various peptides. The myristoylation process is a co-translation that occurs after removing the initiator methionine. This process regulates the assembly of protein complexes and stability, which justifies its potential as a drug target. In order to propose NMT as a potential target for parasitic diseases, this review will address the entire structure and function of this enzyme and the primary studies demonstrating its promising potential against Leishmaniasis, T. cruzi, T. brucei, and malaria. We hope our information can help researchers worldwide search for potential drugs against these diseases that have been threatening the health of the world's population.
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•N-myristoylation is an essential physiological process, as crucial body proteins related to signal regulation and transduction must be myristoylated.•Intervening in the myristoylation process of proteins by inhibiting N-myristoyltransferase may generate new opportunities in drug design.•Drug design against N-myristoyltransferase is based on interaction with residues of His219, Asn376, Ser330, Tyr217, and Leu410 for Leishmaniasis; and His213, Asn365, Ser319, Tyr211, and Leu421 for Plasmodium.•The analogs of pyrazolyl-sulfonamide and benzofurans show their potential as the most potent N-myristoyltransferase inhibitors.•The analog DDD85646 remains the most active compound against N-myristoyltransferase and with the highest target selectivity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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