ABSTRACT
BACKGROUND: Tuberculosis (TB) is one of the top ten causes of death worldwide, while Chagas disease (CD) is the parasitic disease that kills the largest number of people in the Americas. TB is the leading cause of death for patients with AIDS; it kills 1.5 million people and causes 10 million new cases every year. The lack of newly developed chemotherapeutic agents and insufficient access to health care services for a diagnosis increase the incidence of multidrug-resistant TB (MDRTB) cases. Although CD was identified in 1909, the chronic stages of the disease still lack adequate treatment. OBJECTIVE: The purpose of this work was to design and synthesize two new series of 2-nitroimidazole 5a-e and imidazooxazoles 6a-e with 1H-1,2,3-triazolil nucleus and evaluate their activities against Tc and Mycobacterium tuberculosis (Mtb). METHODS: Two series of five compounds were synthesized in a 3 or 4-step route in moderated yields, and their structures were confirmed by NMR spectral data analyses. The in vitro antitrypanosomal evaluation of products was carried out in an intracellular model using L929 cell line infected with trypomastigotes and amastigote forms of Tc of ß-galactosidase-transfected Tulahuen strain. Their antimycobacterial activity was evaluated against Mtb strain H37Rv. RESULTS: In general, 2-nitroimidazolic derivatives proved to be more potent in regard to antitrypanocidal and antimycobacterial activity. The non-cytotoxic 2-nitroimidazole derivative 5b was the most promising with a half maximum inhibitory concentration of 3.2 µM against Tc and a minimum inhibitory concentration of 65.3 µM against Mtb. CONCLUSION: Our study reinforced the importance of 2-nitroimidazole and 1H-1,2,3-triazole nuclei in antimicrobial activity. In addition, derivative 5b proved to be the most promising, presenting important activity against Tc and Mtb and could be used as a starting point for the development of new agents against these diseases.
Subject(s)
Mycobacterium tuberculosis , Nitroimidazoles , Trypanosoma cruzi , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Humans , Microbial Sensitivity Tests , Nitroimidazoles/pharmacologyABSTRACT
Ten 1-phenyl-1H-pyrazolo[3,4-b]pyridine derivatives connected by a linker group to benzenesulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. These ten compounds exhibited activity in vitro against the chloroquine-resistant clone W2 with IC50 values ranging from 3.46 to 9.30µM. The most active derivatives with substituent R2=Cl or CH3 at the benzenesulfonamide moiety exhibited the lowest IC50. Compounds with an R1=CO2Et substituent at the 5-position of the 1H-pyrazolo[3,4-b]pyridine ring presented lower activity than those with a CN substituent. The 1H-pyrazolo[3,4-b]pyridine system appears to be promising for further studies as an antimalarial for overcoming the burden of resistance in P. falciparum.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Pyrazoles/pharmacology , Pyridines/pharmacology , Sulfonamides/pharmacology , Animals , Antimalarials/chemistry , Drug Design , Inhibitory Concentration 50 , Pyrazoles/chemistry , Pyridines/chemistry , Spectrum Analysis/methods , Sulfonamides/chemistryABSTRACT
In this research, a series of substituted 5-(5-amino-1-aryl-1H-pyrazol-4-yl)-1H-tetrazoles were synthesized and evaluated for in vitro antileishmanial activity. Among the derivatives, examined compounds 3b and 3l exhibited promising activity against promastigotes and amastigotes forms of Leishmania amazonensis. The cytotoxicity of these compounds was evaluated on murine cells, giving access to the corresponding selectivity index (SI).
Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Tetrazoles/chemistry , Tetrazoles/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Line , Cell Survival/drug effects , Mice , Mice, Inbred BALB C , Tetrazoles/chemical synthesisABSTRACT
A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a-m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a-m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC50/24h=15±0.14 µM) and 3,4-dichlorophenyl tetrazoles (4d) (IC50/24h=26±0.09 µM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC50=13±0.04 µM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.
Subject(s)
Leishmania/drug effects , Nitriles/chemistry , Pyrazoles/chemistry , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Animals , Antiprotozoal Agents , Cell Line , Dose-Response Relationship, Drug , Mice , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Leishmaniasis is a neglected disease responsible for about 56,000 deaths every year. Despite its importance, there are no effective, safe and proper treatments for leishmaniasis due to strain resistance and/or drug side-effects. In this work we report the synthesis, molecular modeling, cytotoxicity and the antileishmanial profile of a series of 4-(1H-pyrazol-1-yl)benzenesulfonamides. Our experimental data showed an active profile for some compounds against Leishmania infantum and Leishmania amazonensis. The profile of two compounds against L. infantum was similar to that of pentamidine, but with lower cytotoxicity. Molecular modeling evaluation indicated that changes in electronic regions, orientation as well as lipophilicity of the derivatives were areas to improve the interaction with the parasitic target. Overall the compounds represent feasible prototypes for designing new molecules against L. infantum and L. amazonensis.
Subject(s)
Leishmania infantum/drug effects , Leishmania mexicana/drug effects , Sulfonamides/pharmacology , Trypanocidal Agents/pharmacology , Animals , Cell Survival/drug effects , Cells, Cultured , Drug Evaluation, Preclinical , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/physiology , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Conformation , Pentamidine/pharmacology , Quantum Theory , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
In the title compound, C(16)H(13)ClN(4)S, the thienopyridine fused-ring system is nearly planar (r.m.s. deviation = 0.0333â Å) and forms a dihedral angle of 4.4â (3)° with the attached dihydro-imidazole ring (r.m.s. deviation = 0.0429â Å) allowing for the formation of an intra-molecular (exocyclic amine)N-Hâ¯N(imine) hydrogen bond. The benzene rings of the disordered (50:50) -N(H)-C(6)H(4)Cl residue form dihedral angles of 59.1â (3) and 50.59â (15)° with the fused ring system. In the crystal, (imidazole amine)N-Hâ¯N(pyridine) hydrogen bonds lead to a supra-molecular helical chain along the b axis. The chains assemble into layers (ab plane) with inter-digitation of the chloro-benzene rings which results in weak C-Hâ¯Cl inter-actions in the c-axis direction.
ABSTRACT
In the title compound, C(14)H(9)FN(2)O(2)S, the thieno[2,3-b]pyridine residue is almost planar (r.m.s. deviation = 0.0194â Å), with the carb-oxy-lic acid group [dihedral angle = 11.9â (3)°] and the benzene ring [71.1â (4)°] being twisted out of this plane to different extents. An intra-molecular N-Hâ¯O(carbon-yl) hydrogen bond closes an S(6) ring. Supra-molecular chains along [01-1] mediated by O-Hâ¯N(pyridine) hydrogen bonds feature in the crystal. A three-dimensional architecture is completed by π-π inter-actions occurring between the benzene ring and the two rings of the thieno[2,3-b]pyridine residue [centroid-centroid distances = 3.6963â (13) and 3.3812â (13)â Å]. The F atom is disordered over the two meta sites in a near statistical ratio [0.545â (5):0.455â (5)].
ABSTRACT
A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 µM. The reference drug pentamidine presented IC(50)=10 µM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Imidazoles/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/therapeutic use , Leishmania/drug effects , Leishmaniasis/drug therapy , Mice , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Structure-Activity RelationshipABSTRACT
Newly synthesized pyrazole carbohydrazide derivatives with substituents X = Br/Y = NO(2) and X = NO(2)/Y = Cl were independently investigated in the CBA mouse model of cutaneous leishmaniasis. Animals were infected with Leishmania amazonensis and treated two weeks after the parasitic infection with the pyrazole carbohydrazides for 45 days. Oral treatment with both compounds controlled evolution of footpad cutaneous lesions and dissemination of parasites to draining lymph nodes. Nitric oxide generation was observed in supernatants of lymph node cells from infected CBA mice that were treated with these compounds. The pyrazole carbohydrazide derivatives did not show any toxicity or cause alterations in body weight, plasma concentrations of alanine aminotransferase and aspartate aminotransferase, and urinary creatinine levels, but promoted a small decrease in blood neutrophils. These results provide new perspectives on the development of drugs with activities against leishmaniasis.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Hydrazines/chemistry , Leishmania mexicana/drug effects , Leishmaniasis/drug therapy , Pyrazoles/chemistry , Alanine Transaminase/metabolism , Animals , Antiprotozoal Agents/pharmacology , Aspartate Aminotransferases/metabolism , Body Weight/drug effects , Creatinine/blood , Hydrazines/pharmacology , Hydrazines/therapeutic use , Lymph Nodes/parasitology , Lymphocytes , Male , Mice , Mice, Inbred CBA , Molecular Structure , Neutrophils , Pyrazoles/pharmacology , Pyrazoles/therapeutic useABSTRACT
Bacterial infections are a significant cause of morbidity and mortality among critically ill patients. The increase of antibiotic resistance in bacteria from human microbiota-such as Staphylococcus epidermidis, an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices-increased the desire for new antibiotics. In this study we designed, synthesized, and determined the antimicrobial activity of 27 thieno[2,3-b]pyridines (1, 2, 2a-2m, 3, 3a-3m) derivatives against a drug-resistant clinical S. epidermidis strain. In addition, we performed a structure-activity relationship analysis using a molecular modeling approach, and discuss the drug absorption, distribution, metabolism, excretion, and toxicity profile and Lipinski's "rule of five," which are tools to assess the relationship between structures and drug-like properties of active compounds. Our results showed that compound 3b (5-(1H-tetrazol-5-yl)-4-(3;-methylphenylamino)thieno[2,3-b]pyridine) was as active as oxacillin and chloramphenicol but with lower theoretical toxicity risks and a better drug likeness and drug score potential than chloramphenicol. All molecular modeling and biological results reinforced the promising profile of 3b for further experimental investigation and development of new antibacterial drugs.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Design , Drug Resistance, Bacterial , Staphylococcal Infections/drug therapy , Staphylococcus epidermidis/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Bacteria/drug effects , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Models, Molecular , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Staphylococcal Infections/microbiology , Structure-Activity RelationshipABSTRACT
Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a-m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a-m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure-activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates.
Subject(s)
Anti-Bacterial Agents/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Staphylococcus epidermidis/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Bacterial/drug effects , Humans , Leukocytes, Mononuclear/drug effects , Microbial Sensitivity Tests , Models, Molecular , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Reference Values , Staphylococcus epidermidis/growth & development , Structure-Activity Relationship , Time FactorsABSTRACT
Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.
Subject(s)
Acridines/chemistry , Antiviral Agents/chemistry , Herpesvirus 1, Human/drug effects , Naphthyridines/chemistry , Naphthyridines/pharmacology , Acridines/pharmacology , Acridones , Antiviral Agents/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Structure-Activity RelationshipABSTRACT
1H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new compounds (ketoconazole, benznidazole, allopurinol and pentamidine) were also tested. It was found that among all the 1H-pyrazole-4-carbohydrazides derivatives examined, the most active compounds were those with X = Br, Y = NO2 (27) and X = NO2, Y = Cl (15) derivatives which showed to be most effective on promastigotes forms of L. amazonensis than on L. chagasi and L. braziliensis species. When tested against murine peritoneal macrophages as mammalian host cell controls of toxicity, 1-(4-Br-phenyl)-N'-[(4-NO(2)-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (27) (EC50 = 50 microM l(-1)) and 1-(4-NO2-phenyl)-N'-[(4-Cl-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (15) EC50 = 80 microM l(-1))] was reasonably toxic. However, both compounds were less toxic than pentamidine and ketoconazole. These results provide new perspectives on the development of drugs with activities against Leishmania parasite.