Amine-Carbamate Self-Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads.

Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.

Syntheses of α(2,8) Sialosides Containing NeuAc and NeuGc by Using Double Carbonyl-Protected N-Acyl Sialyl Donors.

We report on the syntheses of NeuAc and NeuGc-containing glycosides via the use of double carbonyl-protected N-acetyl sialyl donors. The 7-O,9-O-carbonyl protection of an N-acyl-5-N,4-O-carbonyl-protected sialyl donor markedly increased the α-selectivity during glycosylation, particularly when glycosylating the C-8 hydroxyl group of sialic acids. The N-acyl carbamates were selectively opened with ethanethiol under basic conditions to provide N-acyl amines. It is noteworthy that N-glycolyl carbamate was more reactive to nucleophiles by comparison with the N-acetyl carbamate due to the electron-withdrawing oxygen in the N-acyl group and however, allowed selective opening of the carbamates without the loss of N-glycolyl groups. To demonstrate the utility of the approach, we began by synthesizing α(2,3) and α(2,6) sialyl galactosides. Glycosylation of the hydroxy groups of galactosides at the C-6 position with the NeuAc and NeuGc donors provided the corresponding sialyl galactoses in good yields with excellent α-selectivity. However, glycosylation of the 2,3-diol galactosyl acceptor selectively provided Siaα(2,2)Gal. Next, we prepared a series of α(2,8) disialosides composed of NeuAc and NeuGc. Glycosylation of NeuGc and NeuAc acceptors at the C-8 hydroxyl group with NeuGc and NeuAc sialyl donors provided the corresponding α(2,8) disialosides, and no significant differences were detected in the reactivities of these acceptors.

Chemical tolerance related to the ABC transporter gene and DNA methylation in cladocera (Daphnia magna).

We performed multigenerational tests to clarify the chemical tolerance mechanisms of a nontarget aquatic organism, Daphnia magna. We continuously exposed D. magna to a carbamate insecticide (pirimicarb) at lethal or sublethal concentrations (0, 3.8, 7.5, and 15 µg/L) for 15 generations (F0-F14). We then determined the 48 h-EC50 values and mRNA expression levels of acetylcholinesterase, glutathione S-transferase, and ATP (Adenosine triphosphate)-binding cassette transporter (ABCt) in neonates (<24 h old) from F0, F4, F9, and F14. To ascertain the effects of DNA methylation on pirimicarb sensitivity, we measured 5-methylcytosine levels (DNA methylation levels) in neonates of parents in the last generation (F14). In addition, we cultured groups exposed to 0 and 7.5 µg/L (the latter of which acquired chemical tolerance to pirimicarb) with or without 5-azacytidine (de-methylating agent) and determined methylation levels and 48 h-EC50 values in neonates (<24 h old) from the treated parents. The EC50 values (30.3-31.6 µg/L) in F14 of the 7.5 and 15 µg/L groups were approximately two times higher than that in the control (16.0 µg/L). A linear mixed model analysis showed that EC50 and ABCt mRNA levels were significantly increased with generational alterations; further analysis showed that the ABCt mRNA level was positively related to the EC50 . Therefore, ABCt may be associated with altered pirimicarb sensitivity. In addition, the EC50 value and DNA methylation levels in pirimicarb-tolerant clones decreased after exposure to 5-azacytidine, suggesting that DNA methylation contributes to chemical tolerance. These findings improved our knowledge regarding the acquisition of chemical tolerance in aquatic organisms.

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

Rotation-Inversion Isomerization of Tertiary Carbamates: Potential Energy Surface Analysis of Multi-Paths Isomerization Using Boltzmann Statistics.

Potential energy surface (PES) analyses at the SMD[MP2/6-311++G(d,p)] level and higher-level energies up to MP4(fc,SDTQ) are reported for the fluorinated tertiary carbamate N-ethyl-N-(2,2,2-trifluoroethyl) methyl carbamate (VII) and its parent system N,N-dimethyl methyl carbamate (VI). Emphasis is placed on the analysis of the rotational barrier about the CN carbamate bond and its interplay with the hybridization of the N-lone pair (NLP). All rotational transition state (TS) structures were found by computation of 1D relaxed rotational profiles but only 2D PES scans revealed the rotation-inversion paths in a compelling fashion. We found four unique chiral minima of VII, one pair each of E- and Z-rotamers, and we determined the eight unique rotational TS structures associated with every possible E/Z-isomerization path. It is a significant finding that all TS structures feature N-pyramidalization whereas the minima essentially contain sp2 -hybridized nitrogen. We will show that the TS stabilities are affected by the synergetic interplay between NLP/CO2 repulsion minimization, NLP→σ* (CO) negative hyperconjugation, and two modes of intramolecular through-space electrostatic stabilization. We demonstrate how Boltzmann statistics must be applied to determine the predicted experimental rotational barrier based on the energetics of all eight rotamerization pathways. The computed barrier for VII is in complete agreement with the experimentally measured barrier of the very similar fluorinated carbamate N-Boc-N-(2,2,2-trifluoroethyl)-4-aminobutan-1-ol II. NMR properties of VII were calculated with a variety of density functional/basis set combinations and Boltzmann averaging over the E- and Z-rotamers at our best theoretical level results in good agreement with experimental chemical shifts δ(13 C) and J(13 C,19 F) coupling constants of II (within 6 %).

Green magnetic snail shell hydroxyapatite sorbent for reliable solid-phase extraction of pesticides from water samples.

To address sustainability issues, the green synthesis of nanomaterials has recently received considerable attention. This article addresses a novel and cost-effective adsorbent for the extraction of eight phenyl-N-methylcarbamate insecticides from water samples. We first synthesized a magnetite/hydroxyapatite nanocomposite using snail shell powder via an environmental friendly approach. The morphology and physicochemical properties of magnetic hydroxyapatite were characterized by Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. Magnetic extraction parameters were optimized using a Doehlert matrix. Under optimum conditions, the magnetic extraction coupled with a LC-MS method shows good linearity with R2 ≥ 0.9982, suitable intra- and interday precision, and limits of detection and quantification in the range of 0.052-0.093 µg/L and 0.11-0.31 µg/L, respectively. Satisfactory relative recoveries of all carbamates were achieved from fortified water samples in the range of 93.89-101.01%.

Dietary deprivation reduces the deleterious effects of carbaryl on the survival and activity of both catalase and acetylcholinesterase in earthworms.

Dietary restriction (DR) and dietary deprivation (DD) have been shown to be significantly beneficial in terms of lifespan gains and stress alleviation in invertebrate and vertebrate species. Such beneficial effects, however, have yet to be clearly assessed in the presence of chemical stressors. We conducted a comparative evaluation of the toxicity of carbaryl in Eisenia fetida individuals subjected to a full diet (FD), DR and DD. For 14 days, groups of ten worms subjected to FD received 5 g oatmeal, those subjected to DR received 2.5 g oatmeal, and those subjected to DD received 0 g oatmeal weekly. We evaluated concentrations of 0, 7, 14 and 28 mg carbaryl.kg-1 soil and measured effects on survival, reproduction, biomass and biomarkers (Catalase- CAT and acetylcholine esterase- AChE). Carbaryl caused a total inhibition of reproduction in all the treatments. For each diet level, the 14-day LC50 s were higher than 28 mg.kg-1, but the 14-day LC20 s for the earthworms subjected to FD, DR, and DD were 11.24, 20.51 and > 28 mg.kg-1, respectively. This showed that the toxicity of carbaryl consistently decreased with the reduction in nutrients. Carbaryl caused a significant weight loss in the worms subjected to FD in the 7 mg.kg-1 treatment (P = 0.0065). Such weight loss was not found in any of the other treatments and diets. Both CAT and AChE were significantly inhibited in the two highest treatments (P = 0.0071 and P = 0.0073, respectively). Interestingly, the earthworms subjected to DD showed relatively lower biomarker inhibition, indicating a greater tolerance to oxidative and neurotoxic stresses in these starved earthworms. For all endpoints investigated, aside from reproduction, the starved earthworms fared better under carbaryl toxicity than those given the other diets. Overall, a positive correlation was observed between the amount of food and chemical toxicity as mortality rates, AChE and CAT inhibition increased with the increased amount of nutrients given to the worms. These results show that, in the presence of a chemical stressor, the beneficial effects of DR and DD were variably manifest for select lifecycle parameters and biomarker responses, further suggesting dietary reduction as a non-genetic intervention that could help extend lifespan and alleviate stress even under a chemical insult.

Hybridization of antimicrobial oxazolidinones with commercial drugs: A fight against the "superbugs".

Antimicrobial resistance caused by the emergence of antibiotic-resistant microbes, termed as "superbugs," poses a grave healthcare concern in the contemporary era. Though this phenomenon is natural, an incessant use of antibiotics due to their unregulated over-the-counter availability, and a lack of compliance with the legislation seem to be major contributing factors. This phenomenon has further complicated the treatment of common infectious diseases thereby leading to prolonged illness, disability, and even death. In addition, a sizeable impact on the healthcare cost is met due to a prolonged stay at the medical facilities to receive an intensive care. Overall, the gains of "Millennium Development Goals" and the accomplishment of Sustainable Development Goals are at risk due to the emerging antimicrobial resistance. Since an early identification and development of novel antibiotic classes that evade antimicrobial resistance appears improbable, the strategy of hybridization of the existing antibiotics with efficacious pharmacophores and drug molecules with a different mechanism of antimicrobial action can be a silver lining for the management of superbugs. In this regard, we aim to provide a perspective for the applicability of the hybridization of oxazolidinone class of antibiotics with other drugs for evading antimicrobial resistance.

Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2-32) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1-32 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors.

Efficacy of ethyl-4-bromophenyl carbamate on different Rhipicephalus microplus stages implanted in cattle.

The effect of ethyl-4-bromophenyl carbamate on different Rhipicephalus microplus stages implanted in cattle was evaluated using the pen test with infestation chambers. Twelve steers were distributed into four groups (n = 3), each with four chambers (12 chambers per group), where approximately 1,000 R. microplus larvae were placed in each chamber. The chambers of the first group were sprayed with a solution of ethyl-4-bromophenyl carbamate (0.668 mg/mL) on day 2 post-infestation (PI) (exposed larvae). The chambers of the second group were sprayed with the same solution on day 8 PI (exposed nymphs), and the chambers of the third group were sprayed on day 16 PI (exposed adults) with the same solution. The chambers of the fourth group were used as controls. The percentages of engorged females, egg laying, egg production and egg hatching were evaluated in all groups. The percentage of cumulative reduction of hatched larvae was 98.3, 96.1 and 94.4% when larvae, nymph and adult stages were treated, respectively. The average cumulative reduction of hatched larvae, considering the three treated stages, was 96.3%, whereby the reproductive potential of this tick was drastically reduced. In conclusion, ethyl-4-bromophenyl carbamate acted as an ixodicide (lethal effect) when larval stages were sprayed and as a growth regulator when nymphal and adult stages were sprayed. The sum of these effects had a direct impact on the efficacy of the product in the pen test, and future studies will indicate the potential use of this product for tick control.

The Buzz on Insecticides: A Review of Uses, Molecular Structures, Targets, Adverse Effects, and Alternatives.

Insecticides play a critical role in controlling the spread of insect-borne diseases and preserving crop health. These chemical substances are specifically formulated to kill or manage insect populations. Over the years, various types of insecticides have been developed, including organophosphates, carbamates, pyrethroids, and neonicotinoids, each with unique modes of action, physiological targets, and efficacy. Despite the advantages that insecticides offer, it is imperative to recognize the potential consequences on non-target species, the environment, and human health. It is therefore crucial to follow recommended label instructions and employ integrated pest management practices for the judicious use of insecticides. This review article provides an in-depth examination of the various types of insecticides, including their modes of action, physiological targets, environmental and human health impacts, and alternatives. The aim is to furnish a comprehensive overview of insecticides and to emphasize the significance of responsible and sustainable utilization.

Non-carcinogenic health risk from carbamate pesticide exposure of toddlers living in agricultural areas of Thailand.

Toddlers in agricultural areas may be athave risk from pesticide exposure . A cross-sectional study was conducted with 130 toddlers and their caregivers. Face-to-face interviews were done to gather information about exposure factors. A wipe sampling technique was used to collect carbamate residues on each toddler's hands and feet. Results showed that there were carbamate residues on all wipe samples (100%), with a median concentration of 30.47 micrograms per sample (hands and feet). Carbamate residues detected on toddlers' hands and feetwere significantly associated (p < 0.05) with many factors, including the toddlers' relationships with caregivers, the education level of caregivers, the household incomes, the gender of toddlers, the frequency of following caregivers to farms, the frequency of foot washing, daytime activities, and playing durations. The health risk from dermal carbamate exposurewas above the acceptable range (HI = 3.244). Preventive measures should be considered to reduce toddlers' pesticide exposure in agricultural areas.

Application of pesticide in paddy fields: a Southeast Asia case study review.

Pesticides are widely employed in rice crops since the ecosystem and surroundings of paddy promote insects, weeds, and fungal and bacterial pathogens. Each commonly utilised pesticide possesses different uses. For instance, fungicides control fungal issues, herbicides curb weed growth, and insecticides destroy and repel insects. Although several ways to categorise them exist, pesticides are typically classified according to their chemical compositions. Rice production remains one of the most dominant crops grown in most Southeast Asian countries as it is a staple food. Nonetheless, the crop is highly dependent on pesticides, leading to growing concerns over the potential adverse effects of pesticides on the environment and human health. Despite the availability of numerous studies on the subject, a comprehensive understanding of the specific effects of pesticides on paddy fields in Southeast Asia is still lacking. Consequently, reviewing existing knowledge is necessary for synthesising and identifying research gaps to better inform policymakers, farmers, and other stakeholders in the agricultural sector. The objectives of the present review paper were to review the interactions between pesticides and the environment by understanding the physical and chemical properties of the chemicals, compare pesticide transportation modes in air, water, and soil and how they affect the environment, and evaluate and discuss the effects of pesticides on non-targeted organisms. This study assessed pesticide innovation reported between 1945 and 2021 for a better understanding of the utilisation of the chemicals over time. The pesticides assessed in this study were classified based on their chemical compounds, such as organochlorines, organophosphates, carbamates, and pyrethroid. This review could provide a comprehensive understanding of the interactions between pesticides and the environment and their impacts on non-targeted organisms.

Silver-Mediated Cascade Synthesis of Functionalized 1,4-Dihydro-2H-benzo-1,3-oxazin-2-ones from Carbon Dioxide.

A conceptually novel catalytic domino approach is presented for the synthesis of highly functional 1,4-dihydro-2H-1,3-benzoxazine-2-one derivatives. Key to the chemoselectivity is a proper design of the precursor to override thermodynamically favored parasitic cyclization processes and empower the formation of the desired product through Thorpe-Ingold effects. The synthetic diversity of these CO2 -based heterocycles is further demonstrated, and the isolation of a reaction intermediate supports an unusual ring-expansion sequence from an α-alkylidene, five-membered cyclic carbonate to a six-membered cyclic carbamate by N-induced isomerization.

2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands.

Ligands comprising a benzimidazole rather than the imidazole ring that is common in AT2R ligands e.g. in the AT2R agonist C21, can provide both high affinity and receptor selectivity. In particular, compounds encompassing benzimidazoles, substituted in the 2-position with small bulky groups such as an isopropyl (Ki = 4.0 nM) or a tert-butyl (Ki = 5.3 nM) or alternatively a thiazole heterocycle (Ki = 5.1 nM) demonstrate high affinity and AT2R selectivity. An n-butyl chain, as found in the AT1R selective sartans, makes the ligand less receptor selective. The isobutyl group on the biaryl scaffold present in most AT2R selective ligands reported so far was originally derived from the nonselective potent AT1R/AT2R ligand L-162,313. Notably, in all ligands discussed herein, the isobutyl group was substituted by an n-propyl group and ligands with high affinity to AT2R were provided and in addition the majority of them demonstrate a favorable AT2R/AT1R selectivity. The introduction of fluoro atoms in various positions had no pronounced effect on the affinity data. Ligands with a thiazole or a tert-butyl group attached to the 2-position and with a terminal trifluoromethyl butoxycarbonyl sidechain exhibited a similar stability as C21 in human liver microsomes, while other ligands examined were less stable in the microsome assay.

Amide directed iridium C(sp3)-H borylation catalysis with high N-methyl selectivity.

A bidentate monoanionic ligand system was developed to enable iridium catalyzed C(sp3)-H activation borylation of N-methyl amides. Borylated amides were obtained in moderate to good isolated yields, and exclusive mono-borylation allowed the amide to be the limiting reagent. Selectivity for C(sp3)-H activation was demonstrated in the presence of sterically available C(sp3)-H bonds. Competitive kinetic isotope studies revealed a large primary isotope effect, implicating C-H activation as the rate limiting step.

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.

Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl)phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.

Benzimidazole-carbamate anthelmintics: Perspective candidates for the anticancer drug development.

Cellular oncogenesis involves a complex interplay between the several synchronized, interdependent pathways that collectively determine the pathogenesis and pathophysiology of cancer. Limited therapeutic success with the existing anticancer drugs drew huge interest in the design and development of new pharmacophores with improved clinical efficacy, however despite huge investments in anticancer RD; the average number of Food and Drug Administration-approved anticancer drugs declined since the 1990s. The contemporary anticancer medications possess high attrition rates, bear substantial costs, and experience low efficacy owing to the drug resistance expressed by the aggressive tumors. Mainly, the translation of novel candidate anticancer drugs into clinical practice, their commercialization, and transformation from the bench to bedside require a long timeframe of 10-15 years and capital worth millions of dollars. The repurposing strategy substantially accelerated the anticancer drug development regime as the approved drugs with tested safety and efficacy ensure a minimal risk of failure, and nominal R&D expenses as anticipated for the newly identified candidate drugs yet to enter the clinical trials. In addition, the repurposed drugs ensure a rapid clinical translation due to a validated clinical profile and their ability to target the identified hallmarks and hitherto unknown vulnerabilities of cancer. The flagship project "Repurposing Drugs in Oncology" (ReDO) identified 268 "hard repurposing" noncancer medications as candidate drugs with a promising anticancer profile (https://www.anticancerfund.org/en/redo-db). However, the generic profile of 84% of repurposed drugs in ReDO data set discourages the commercial sponsors from funding the repurposing trials, especially the Phase III efficacy trials that require significant capital.

Synthesis of Four Steroidal Carbamates with Antitumor Activity against Mouse Colon Carcinoma CT26WT Cells: In Vitro and In Silico Evidence.

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.

Double Repositioning: Veterinary Antiparasitic to Human Anticancer.

Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for "double repositioning", as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments.