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Amblyomma sculptum is a relevant tick species from a One Health perspective, playing an important role as a vector of Rickettsia rickettsii, the main agent of spotted fever rickettsiosis in Brazil. In this study, we evaluated the susceptibility of two A. sculptum populations from Goiás state (midwestern Brazil) to different acaricides. The first tick population (GYN strain) originated from an experimental farm, where the ticks are annually exposed to acaricides. The second (PNE strain) was collected in a national park (Emas National Park), where the ticks had not been exposed to acaricides. Immersion tests were conducted with 21-day-old laboratory-reared larvae and nymphs originating from adult ticks collected in the areas mentioned above. The chosen acaricides were two synthetic pyrethroids (cypermethrin and deltamethrin), one organophosphate (chlorfenvinphos), one formamidine (amitraz), and two combinations of pyrethroids and organophosphates (cypermethrin, chlorpyrifos and citronellal; cypermethrin, fenthion and chlorpyrifos). Mortality data were used to determine the lethal concentration (LC) values at which 50%, 90%, and 99% of the ticks died (LC50, LC90, and LC99, respectively), and resistance ratios (RR) were calculated based on the LC values. The RR revealed differences between the acaricide-exposed (GYN) and unexposed (PNE) tick strains. The PNE strain larvae and nymphs were susceptible to all the tested acaricides. The GYN strain larvae were tolerant to cypermethrin, whereas the nymphs were tolerant to deltamethrin, chlorfenvinphos, and the combination of cypermethrin, chlorpyrifos, and citronellal (2 < RR ≤ 10). The GYN strain nymphs were resistant to amitraz (RR > 10). This is the first report of A. sculptum nymphs with resistance to amitraz and tolerance to deltamethrin, chlorfenvinphos, and the combination of cypermethrin, chlorpyrifos, and citronellal.
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Aim: The aim was synthesis of novel benzazoles bearing amidino and 2-hydroxyphenyl substituents to explore their biological activity. Methods: Condensation of 5-substituted salicylaldehydes and intermediates gave new benzazoles by previously published and developed procedures, which were tested for antibacterial and antiproliferative activity in vitro. Results: The best antibacterial activity showed benzimidazole with 2-imidazolinyl group 27 and benzothiazole with an unsubstituted amidine 48 (minimum inhibitory concentration 8 µg/ml). Benzothiazole 53 proved most potent at inhibiting proliferation of all cancer cells (IC50: 1.2-2.0 µM). Conclusion: Most active compounds have been recognized as lead compounds for additional optimization to improve their biological activity. The type of amidine moiety markedly influenced the biological activity. Benzothiazoles showed improved antiproliferative activity in comparison to benzimidazoles.
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A meeting, sponsored by the Bill and Melinda Gates Foundation (BMGF) and organised by Clinglobal, was held at The International Livestock Research Institute (ILRI) in Nairobi, Kenya, from 19th - to 21st October 2022. The meeting assembled a unique group of experts on tick control in Africa. Academia, international agencies (FAO and ILRI), the private Animal Health sector and government veterinary services were represented. The significant outcomes included: (i) a shared commitment to standardisation and improvement of acaricide resistance bioassay protocols, particularly the widely used larval packet test (LPT); (ii) development of novel molecular assays for detecting acaricide resistance; (3) creation of platforms for disseminating acaricide resistance data to farmers, veterinary service providers and veterinary authorities to enable more rational evidence-based control of livestock ticks. Implementation of enhanced control will be facilitated by several recently established networks focused on control of parasites in Africa and globally, whose activities were presented at the meeting. These include a newly launched community of practice on management of livestock ticks, coordinated by FAO, an African module of the World Association for the Advancement of Veterinary Parasitology (WAAVP-AN) and the MAHABA (Managing Animal Health and Acaricides for a Better Africa) initiative of Elanco Animal Health.
Assuntos
Acaricidas , Doenças dos Bovinos , Rhipicephalus , Infestações por Carrapato , Doenças Transmitidas por Carrapatos , Animais , Bovinos , Acaricidas/farmacologia , Quênia/epidemiologia , Doenças Transmitidas por Carrapatos/epidemiologia , Doenças Transmitidas por Carrapatos/prevenção & controle , Doenças Transmitidas por Carrapatos/veterinária , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/epidemiologia , Infestações por Carrapato/epidemiologia , Infestações por Carrapato/prevenção & controle , Infestações por Carrapato/veterináriaRESUMO
Novel benzo[b]thienyl- and 2,2'-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities inâ vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2'-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2'-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2'-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA.
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Antineoplásicos , Carcinoma , Humanos , Antineoplásicos/química , Linhagem Celular Tumoral , Benzotiazóis/química , DNA/metabolismo , Benzimidazóis/química , Amidinas/farmacologia , Amidinas/química , Relação Estrutura-Atividade , Proliferação de CélulasRESUMO
Pyrimidine is a six-membered diaza-heterocycle i. e., 1,3-diazine. It is found to be present in many biologically and pharmacologically active scaffolds like nucleotides, natural products, and drugs. The bioactivities of pyrimidine include anti-tubercular, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-malarial, anti-cancer, anti-neoplastic and many more. In this review article we have summarized various synthetic approaches that involve the synthesis of these privileged building blocks by employing propargylic alcohols and their derivatives like propargylic esters and propargylic ynones as three carbon-components. Here, we have confined ourselves to the developments appeared during the period of 23â years i. e., 2000-2022.
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Compounds that bind in the DNA minor groove have provided critical information on DNA molecular recognition, have found extensive uses in biotechnology, and are providing clinically useful drugs against diseases as diverse as cancer and sleeping sickness. This review focuses on the development of clinically useful heterocyclic diamidine minor groove binders. These compounds show that the classical model for minor groove binding in AT DNA sequences must be expanded in several ways: compounds with nonstandard shapes can bind strongly to the groove, water can be directly incorporated into the minor groove complex in an interfacial interaction, compounds can be designed to recognize GC and mixed AT/GC base pair sequences, and stacked dimers can form to recognize specific sequences. © 2023 Wiley Periodicals LLC.
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DNA , Ressonância de Plasmônio de Superfície , Sítios de Ligação , DNA/química , DNA/metabolismo , Pareamento de Bases , PentamidinaRESUMO
New analogs of the antiprotozoal agent Furamidine were prepared utilizing Stille coupling reactions and amidation of the bisnitrile intermediate using lithium bis-trimethylsilylamide. Both the phenyl groups and the furan moiety of furamidine were replaced by heterocycles including thiophene, selenophene, indole or benzimidazole. Based upon the ΔTm and the CD results, the new compounds showed strong binding to the DNA minor groove. The new analogues are also more active both in vitro and in vivo than furamidine. Compounds 7a, 7b, and 7f showed the highest activity in vivo by curing 75% of animals, and this merits further evaluation.
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Antiprotozoários , Benzamidinas , Animais , Benzamidinas/farmacologia , Benzamidinas/química , Benzamidinas/metabolismo , Antiprotozoários/farmacologia , DNA/metabolismoRESUMO
Triple negative breast cancer (TNBC) is a specific breast cancer subtype, and poor prognosis is associated to this tumour when it is in the metastatic form. The overexpression of the inducible Nitric Oxide Synthase (iNOS) is considered a predictor of poor outcome in TNBC patients, and this enzyme is reported as a valuable molecular target to compromise TNBC progression. In this work, new amidines containing a benzenesulfonamide group were designed and synthesized as selective iNOS inhibitors. An in vitro biological evaluation was performed to assess compounds activity against both the inducible and constitutive NOSs. The most interesting compounds 1b and 2b were evaluated on MDA-MB-231 cells as antiproliferative agents, and 1b capability to counteract cell migration was also studied. Finally, an in-depth docking study was performed to shed light on the observed potency and selectivity of action of the most promising compounds.
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Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Óxido Nítrico Sintase Tipo II , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Amidinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , BenzenossulfonamidasRESUMO
A new route to 5-amino-1,2,4-thiadiazole derivatives via reaction of N-chloroamidines with isothiocyanates has been proposed. The advantages of this method are high product yields (up to 93%), the column chromatography-free workup procedure, scalability and the absence of additive oxidizing agents or transition metal catalysts. The 28 examples of 5-amino-1,2,4-thiadiazole derivatives obtaining via the proposing protocol were evaluated in vitro against ESKAPE pathogens strains (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae). It was found that compounds 5ba, 5bd, 6a, 6d and 6c have potent antibacterial activity (MIC values 0.09-1.5 µg mL-1), which is superior to the activity of commercial antibiotics such as pefloxacin (MIC 4-8 µg mL-1) and streptomycin (MIC 2-32 µg mL-1). The additional cytotoxic assay of hit compounds on PANC-1 cell line demonstrated the low or non-cytotoxicity activity at the same level of concentrations. Thus, these 5 compounds are promising starting point for further antimicrobial drug development.
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Anti-Infecciosos , Enterococcus faecium , Antibacterianos/farmacologia , Klebsiella pneumoniae , Staphylococcus aureusRESUMO
The novel biocatalytic method for the synthesis of pharmaceutically relevant N-unsubstituted amidines was presented. The application of whole cells from commonly available vegetables allowed for the chemoselective reduction of the amidoxime moiety in the presence of other substituents prone to reduction or dehalogenation e.g. carbon-carbon double bond. Under optimized conditions several amidines were obtained with high yield up to 97% in aqueous medium at ambient temperature and atmospheric pressure. The practical potential of the newly developed method was shown in the preparative synthesis of anti-parasitic drug, phenamidine. Moreover, for the first time the enantioselective bioreduction of chiral racemic amidoximes to the corresponding amidines has been shown. The developed sustainable biocatalytic protocol fulfils the green chemistry rules and no application of metal catalysts meets the strict requirements of the pharmaceutical industry regarding metal contamination.
Assuntos
Oxirredutases , Saccharomyces cerevisiae , Amidinas/química , Biocatálise , Carbono , Oxirredutases/metabolismo , Oximas , Raízes de Plantas/metabolismo , Saccharomyces cerevisiae/metabolismo , EstereoisomerismoRESUMO
A pseudo-three-component synthesis of N-aroylmethylimidazoles 3 with three new C-N bonds formed regioselectively under microwave conditions was developed. Products were obtained by reacting two equivalents of aroylmethyl bromide (ArCOCH2Br, 1) with the appropriate amidine salt (RCN2H3.HX, 2) and with K2CO3 as a base in acetonitrile. The bicomponent reaction also occurred, giving the expected 4(5)-aryl-1H-imidazoles 4. Notably, the ratio of products 3 and 4 is governed by steric factors of the amidine 2 (i.e., R = H, CH3, Ph). Therefore, a computational study was carried out to understand the reaction course regarding product ratio (3/4), regioselectivity, and the steric effects of the amidine substituent group.
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A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC50 0.4 and 0.7 µM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 µM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC50 21 µM), and para-cyano-substituted derivative 17 (EC50 58 µM) showed selective but moderate activity against respiratory syncytial virus (RSV).
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Antineoplásicos , Piridinas , Humanos , Linhagem Celular Tumoral , Piridinas/farmacologia , Escherichia coli , Antineoplásicos/farmacologia , Antibacterianos/farmacologia , Relação Estrutura-Atividade , Proliferação de CélulasRESUMO
The biological research on newly synthesized amidoximes, Boc-protected amidoximes and Boc-derived amidines, obtained by a reduction of the parent amidoximes is reported, herein. Due to the presence of a free amino group in both amidines and amidoximes, these compounds can undergo various chemical reactions such as N-alkylation and N-acylation. One such reaction is Boc-protection, often used in organic synthesis to protect the amino and imino groups. Until now, Boc-protected amidoximes have not been tested for biological activity. Amidoxime derivatives were tested on bacterial E. coli strains. Initial cellular studies tests and digestion with Fpg after the modification of bacterial DNA, suggest that these compounds may have greater potential as antibacterial agents compared to antibiotics such as ciprofloxacin (ci), bleomycin (b) and cloxacillin (cl). The described compounds are highly specific for pathogenic E. coli strains on the basis of the model strains used and may be used in the future as new substitutes for commonly used antibiotics in clinical and hospital infections in the pandemic era.
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The interaction of acetamidine and phenylamidine with peri-R-ethynyl-9,10-anthraquinones in refluxing n-butanol leads to the formation of cascade transformations products: addition/elimination/cyclization-2-R-7H-dibenzo[de,h]quinolin-7-ones and(or) 2-R-3-aroyl-7H-dibenzo[de,h]quinolin-7-ones. The anti-inflammatory and antitumor properties of the new 2-R-7H-dibenzo[de,h]quinolin-7-ones were investigated in vivo, in vitro, and in silico. The synthesized compounds exhibit high anti-inflammatory activity at dose 20 mg/kg (intraperitoneal injection) in the models of exudative (histamine-induced) and immunogenic (concanavalin A-induced) inflammation. Molecular docking data demonstrate that quinolinones can potentially intercalate into DNA similarly to the antitumor drug doxorubicin.
Assuntos
Amidinas/química , Antraquinonas/química , Anti-Inflamatórios/química , Antineoplásicos/química , Quinolinas/química , Alcaloides/síntese química , Alcaloides/química , Alcaloides/farmacologia , Amidinas/síntese química , Animais , Antraquinonas/síntese química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Quinolinas/farmacologiaRESUMO
Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
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Acinetobacter baumannii , Antibacterianos , Amidinas , Antibacterianos/farmacologia , Bactérias Gram-Negativas , Klebsiella pneumoniaeRESUMO
A series of novel cobalt bis(dicarbollide) based amidines were synthesized by the nucleophilic addition of primary and secondary amines to highly activated B-N+≡C-R triple bond of the propionitrilium derivative [8-EtC≡N-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)]. The reactions with primary amines result in the formation of mixtures of E and Z isomers of amidines, whereas the reactions with secondary amines lead selectively to the E-isomers. The crystal molecular structures of E-[8-EtC(NMe2)=HN-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)], E-[8-EtC(NEt2)=HN-3,3'-Co(1,2- C2B9H10)(1',2'-C2B9H11)] and E-[8-EtC(NC5H10)=HN-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)] were determined by single crystal X-ray diffraction.
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N-C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N-C biaryl atropisomers by stereoselective metal-catalyzed aryl amination remains unprecedented. Herein, a Pd-catalyzed cross-coupling strategy is presented for the synthesis of N-C axially chiral biaryl molecules. A broad spectrum of N-C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 %â ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.
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Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection.
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Guanidina/análogos & derivados , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , Ureia/análogos & derivados , Aciclovir/efeitos adversos , Aciclovir/farmacologia , Antivirais/farmacologia , Farmacorresistência Viral/genética , Guanidina/síntese química , Guanidina/farmacologia , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Simplexvirus/genética , Simplexvirus/patogenicidade , Ureia/síntese química , Ureia/farmacologiaRESUMO
Newly designed and synthesized cyano, amidino and acrylonitrile 2,5-disubstituted furane derivatives with either benzimidazole/benzothiazole nuclei have been evaluated for antitumor and antimicrobial activity. For potential antitumor activity, the compounds were tested in 2D and 3D cell culture methods on three human lung cancer cell lines, A549, HCC827 and NCI-H358, with MTS cytotoxicity and BrdU proliferation assays in vitro. Compounds 5, 6, 8, 9 and 15 have been proven to be compounds with potential antitumor activity with high potential to stop the proliferation of cells. In general, benzothiazole derivatives were more active in comparison to benzimidazole derivatives. Antimicrobial activity was evaluated with Broth microdilution testing (according to CLSI (Clinical Laboratory Standards Institute) guidelines) on Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Additionally, Saccharomyces cerevisiae was included in testing as a eukaryotic model organism. Compounds 5, 6, 8, 9 and 15 showed the most promising antibacterial activity. In general, the compounds showed antitumor activity, higher in 2D assays in comparison with 3D assays, on all three cell lines in both assays. In natural conditions, compounds with such an activity profile (less toxic but still effective against tumor growth) could be promising new antitumor drugs. Some of the tested compounds showed antimicrobial activity. In contrast to ctDNA, the presence of nitro group or chlorine in selected furane-benzothiazole structures did not influence the binding mode with AT-DNA. All compounds dominantly bound inside the minor groove of AT-DNA either in form of monomers or dimer and higher-order aggregates.
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Anti-Infecciosos/farmacologia , Benzimidazóis/farmacologia , Benzotiazóis/farmacologia , Neoplasias/tratamento farmacológico , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Relação Estrutura-AtividadeRESUMO
The flavivirus genus of the Flaviviridae family comprises Dengue, Zika and West-Nile viruses which constitute unmet medical needs as neither appropriate antivirals nor safe vaccines are available. The dengue NS2BNS3 protease is one of the most promising validated targets for developing a dengue treatment however reported protease inhibitors suffer from toxicity and cellular inefficacy. Here we report SAR on our previously reported Zika-active carbazole scaffold, culminating prodrug compound SP-471P (EC50 1.10 µM, CC50 > 100 µM) that generates SP-471; one of the most potent, non-cytotoxic and cell-active protease inhibitors described in the dengue literature. In cell-based assays, SP-471P leads to inhibition of viral RNA replication and complete abolishment of infective viral particle production even when administered 6 h post-infection. Mechanistically, SP-471 appears to inhibit both normal intermolecular protease processes and intramolecular cleavage events at the NS2BNS3 junction, as well as at NS3 internal sites, all critical for virus replication. These render SP-471 a unique to date multimodal inhibitor of the dengue protease.