Derivatives 2b Research Articles

Development of novel cyanopyridines as PIM-1 kinase inhibitors with potent anti-prostate cancer activity: Synthesis, biological evaluation, nanoparticles formulation and molecular dynamics simulation

Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b, 3b, 4b, and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC50 = 0.248, 0.13, 0.326 and 0.245 μM, respectively. The most powerful derivatives2b, 3b, 4b, and 5b, were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b–PIM-1 complex has the low binding free energy (−242.2 kJ/mol) according to the MM-PBSA calculations.

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas.

Trifluoroacetic acid (TFA), due to its strong acidity and low boiling point, is extensively used in protecting groups-based synthetic strategies. Indeed, synthetic compounds bearing basic functions, such as amines or guanidines (commonly found in peptido or peptidomimetic derivatives), developed in the frame of drug discovery programmes, are often isolated as trifluoroacetate (TF-Acetate) salts and their biological activity is assessed as such in in vitro, ex vivo, or in vivo experiments. However, the presence of residual amounts of TFA was reported to potentially affect the accuracy and reproducibility of a broad range of cellular assays (e. g. antimicrobial susceptibility testing, and cytotoxicity assays) limiting the further development of these derivatives. Furthermore, the impact of the counterion on biological activity, including TF-Acetate, is still controversial. Herein, we present a focused case study aiming to evaluate the activity of an antibacterial AlkylGuanidino Urea (AGU) compound obtained as TF-Acetate (1a) and hydrochloride (1b) salt forms to highlight the role of counterions in affecting the biological activity. We also prepared and tested the corresponding free base (1c). The exchange of the counterions applied to polyguanidino compounds represents an unexplored and challenging field, which required significant efforts for the successful optimization of reliable methods of preparation, also reported in this work. In the end, the biological evaluation revealed a quite similar biological profile for the salt derivatives 1a and 1b and a lower potency was found for the free base 1c.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11030-022-10505-6.

Green Method Synthesis of Pyrano[2,3-d]Pyrimidine Derivatives: Antimicrobial and Electrochemical Behavior Studies

The present work describes one-pot synthesis of pyrano[2,3-d] pyrimidine derivatives using aromatic aldehyde, ethyl cyanoacetate and barbituric or thiobarbituric acid accelerated by microwave irradiation in the presence of agro-waste extract solvent medium with few drops of ethanol as a co-solvent presented. The reaction is optimized by various methods such as magnetic stirring, ultrasound, mechanochemical and microwave irradiation, but the microwave irradiation method excelled product formation faster rate with high yield and purity. The advantages of the present approach are the metal-free, chemical-less, and hazardous solvent-less employed and considered as an eco-friendly protocol for the synthesis of pyrano[2,3-d] pyrimidine derivatives developed. The final product isolated was recrystallized in ethanol and characterized by FT-IR, 1H-, 13C-NMR and LC-MS spectrometry. Further, some of the selected pyrano[2,3-d]pyrimidine derivatives (4a, 4b, 4d, 4f, 4m and 4o) are subjected to electrochemical behavior and anti-microbial activity studies. The anti-microbial activity tested derivatives showed comparable activities, and also electrochemical behavior of oxidation and reduction potentials observed by these compounds.

Experimental and theoretical studies on prototropic tautomerism of 1-tetralone-2-carbothioamides and synthesis of regioselectively designed fused 2H-indazole derivatives

Condensation of 1-tetralones with phenylisothiocyanate in presence of sodium hydride produced 1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carbothioamides 2a–b. The structure of carbothioamides 2 was established on the basis of spectral data. Prototropic tautomerism studies of carbothioamide 2a were investigated in solution by NMR (1H and 13C NMR), electronic spectroscopy and gas chromatography techniques. The proton transfer behaviour in solid state and gaseous phase was studied utilizing FT-IR and Mass spectral studies, respectively. DFT approach was used to accomplish the theoretical computations. The ground state geometries of different tautomers were optimized using B3LYP method and 6-31G(d) basis set. The vibrational and NMR spectra of different tautomers were calculated and correlated with the experimental results. HOMO-LUMO studies of different probable tautomers of carbothioamide 2a were employed in determination of chemical reactivity descriptors.The dynamic photoisomerization experiments were performed in chloroform under UV irradiation (UV lamp, 15W) and spectra were recorded to investigate the photo dynamic keto ⇌ enol ⇌ thioenol tautomerization. Further, condensation of carbothioamides 2 with hydrazine and its aryl derivatives regioselectively furnished 4,5-dihydro-2H-benzo[g]indazole derivatives 3. Spectrochemical characterizations and single crystal X-ray diffraction analysis of representative indazole derivative 3b resolved the structural ambiguity between the possible 2H-indazole 3 and 1H-indazole 4 regioisomers. Also, the optimized geometric bond lengths and bond angles, obtained by using DFT studies, were compared with the values obtained from X-ray diffraction. The regioselectivity of 3 was justified by root mean square deviations (RMSD) calculations which shows the minimum deviation for 2H-indazole derivative 3.

Synthesis and structure of polycyclic 1,2,3-triazolylmethyl-benzimidazole derivatives — Experimental and computational quantum chemical studies

Three novel triazolo-benzimidazolyl derivatives have been designed and efficiently synthesized via Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between the N-propargyl benzimidazole and diverse arylazides. Compounds (6a-c) were characterized by spectroscopic techniques (1H and 13C NMR) and the solid-state structure of derivative 6b was elucidated by X-ray crystallography. The compound crystallizes in the triclinic system with P-1 space group, as single molecule in the asymmetric unit. The supramolecular conformation is stabilized by miscellaneous network of intermolecular interactions, mainly C—H…N(O) H-bonds. The nature and energetics of key non-covalent interactions were analysed based on the Hirshfeld surface and further confirmed through Atoms-In-Molecules (AIM) topological technique. Moreover, Mappings of electrostatic potential (MEP) and Parr functions were used for the identification of the probable reactive sites.

Synthesis of Novel 2,3-Dihydro-1,5-Benzothiazepines as α-Glucosidase Inhibitors: In Vitro, In Vivo, Kinetic, SAR, Molecular Docking, and QSAR Studies.

In the present study, a series of 2,3-dihydro-1,5-benzothiazepine derivatives 1B–14B has been synthesized sand characterized by various spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using in vitro and in vivo mechanism-based assays. The tested compounds 1B–14B exhibited in vitro inhibitory potential against α-glucosidase with IC50 = 2.62 ± 0.16 to 10.11 ± 0.32 μM as compared to the standard drug acarbose (IC50 = 37.38 ± 1.37 μM). Kinetic studies of the most active derivatives 2B and 3B illustrated competitive inhibitions. Based on the α-glucosidase inhibitory effect, the compounds 2B, 3B, 6B, 7B, 12B, 13B, and 14B were chosen in vivo for further evaluation of antidiabetic activity in streptozotocin-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic activity and were found to be nontoxic in nature. Moreover, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of the α-glucosidase enzyme (PDB ID 3AJ7). Additionally, quantitative structure–activity relationship (QSAR) studies were performed based on the α-glucosidase inhibitory assay. The value of correlation coefficient (r) 0.9553 shows that there was a good correlation between the 1B–14B structures and selected properties. There is a correlation between the experimental and theoretical results. Thus, these novel compounds could serve as potential candidates to become leads for the development of new drugs provoking an anti-hyperglycemic effect.

Development of retinoic acid receptor antagonists bearing trans-SF4-alkynyl structure as a linear linker

transTetrafluoro-λ6-sulfane (tetrafluorosulfanyl, SF4) compounds possess unique properties, including a linear structure and high electronegativity. Here, to investigate the utility of the trans-SF4 moiety as a structural element of bioactive compounds, we designed and synthesized novel retinoids containing a trans-SF4-alkynyl group as a linear linker. The radical addition reaction of aryltetrafluorosulfanyl chloride and arylethyne, followed by elimination of hydrogen chloride, afforded the target compounds 1a – 1c. Cell differentiation-inducing activity assay and reporter gene assay revealed that the trans-SF4-alkynyl derivatives 1b and 1c exhibit antagonistic activity towards retinoid acid receptors (RARs). Docking studies suggested that the long and linear linker alters the binding mode of 1b with the RARα ligand-binding domain.

N'-Substituted 4-Phenylpicolinohydrazonamides with Thiosemicarbazone Moiety as New Potential Antitubercular Agents: Synthesis, Structure and Evaluation of Antimicrobial Activity.

Three new 4-phenylpicolin derivatives with a thiosemicarbazone structure were synthesized and evaluated for tuberculostatic activity. The compounds were obtained by the condensation of methyl 4-phenylpicolonimidate with the corresponding cycloalkylamino-1-carbothiohydrazides. The 1H NMR temperature spectra obtained showed proton lability at the nitrogen atom N2, and X-ray crystallography confirmed the zwitterionic structure of all products. ADME calculations indicate that the compounds can be tested as future drugs. All compounds were absorbed in the gastrointestinal tract. All compounds also showed very good tuberculostatic activity (MIC 3.1–12.5 µg/mL). Derivative 1b showed the best selectivity for M. tuberculosis compared to the other pathogenic species tested. The study has allowed the emergence of imine derivative 1b as a good structure for further optimization in the search for antitubercular drugs.

Catalytic and Multicomponent Reactions for Green Synthesis of Some Pyrazolone Compounds and Evaluation as Antimicrobial Agents.

A green synthetic approach and facile method was developed to produce pyrazole compounds (6a–d) by the reaction of ethyl acetoacetate (1), hydrazines (2a–d), and catalytic imidazole (3) in aqueous media. 4-Dicyanomethylene-2-pyrazoline-5-one derivatives (14a–d) were synthesized through the reaction of 2-pyrazoline-5-one derivatives (6a–d) with tetracyanoethylene (TCE) (7) by using catalytic imidazole (3) in an aqueous medium. Moreover, the 4-dicyanomethylene derivative (16) was obtained via treatment of 1-phenyl-3,5-pyrazolidinedione (15) with TCE (7). The spiropyrazoleoxirane derivatives (18 and 20) were prepared by treating the precursor 4-dicyanomethylene-2-pyrazoline-5-one derivative (14b) with hydrogen peroxide in various polar solvents under alkaline conditions. The spiropyrazole oxirane derivative (18) was used as a precursor for the design of functionalized pyrazolone derivatives (24 and 27a, b). The chemical structure of the novel designed derivatives was ascertained based on elemental analyses, mp, thin-layer chromatography, and spectral analyses. Furthermore, some of the synthesized derivatives were examined against different pathogenic bacterial and fungal strains. Their results demonstrated that some of them revealed notable antimicrobial activities.

Discovery of C20-Diterpenoid Alkaloid Kobusine Derivatives Exhibiting Sub-G1 Inducing Activity.

Although many diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human cancer cell lines, little data have been offered relating to the antiproliferative effects of hetisine-type C20-diterpenoid alkaloids, such as kobusine (1), likewise as their derivatives. A total of 43 novel diterpenoid alkaloid derivatives (2–10, 2b, 3a, 3b, 6a–16a, 7b, 9b, 10b, 13, 15–26, 15b, 18a, 23a, 27a) were prepared by C-11 and -15 esterification of 1. Antiproliferative effects of the natural parent compound (1) and all synthesized kobusine derivatives against human cancer cell lines, including a triple-negative breast cancer (TNBC) cell line as well as a P-glycoprotein overexpressing multidrug-resistant subline, were assessed. The structure-based design strategy resulted in the lead derivative 11,15-dibenzoylkobusine (3; average IC50 7.3 μM). Several newly synthesized kobusine derivatives (particularly, 5–8, 10, 13, 15–26) exhibited substantial suppressive effects against all tested human cancer cell lines. In contrast, kobusine (1), 11,15-O-diacetylkobusine (2), 11-acylkobusine derivatives (3a, 6a, 9a, 11a, 12a, 15a, 27a), and 15-acylkobusine derivatives (2b, 3b, 7b, 9b, 10b, 15b) showed no effect. The most active kobusine derivatives primarily had two specific substitution patterns, C-11,15 and C-11. Notably, 11,15-diacylkobusine derivatives (3, 6–10, 13, 15, 16, 18, 23) were more potent compared with 11- and 15-acylkobusine derivatives (3a, 3b, 6a–10a, 7b, 9b, 10b, 13a, 15a, 15b, 16a, 18a, 23a). Derivatives 13 and 25 induced MDA-MB-231 cells to the sub-G1 phase within 12 h. 11,15-Diacylation of kobusine (1) appears to be crucial for inducing antiproliferative activity in this alkaloid class and could introduce a new avenue to overcome TNBC using natural product derivatives.

Cytotoxic Evaluation and Molecular Docking Studies of Aminopyridine Derivatives as Potential Anticancer Agents.

The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure. The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2- aminopyridine could attenuate tumor development using colorectal cancer cell lines. Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay. The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1μM and 3.27-7.7 μM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 μg/ml. In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.

Tackling Microbial Resistance with Isatin-Decorated Thiazole Derivatives: Design, Synthesis, and in vitro Evaluation of Antimicrobial and Antibiofilm Activity.

IntroductionAntibiotic resistance is a global threat that has been increasing recently, especially with antibiotic overuse and misuse. The search for new antibiotics is becoming more and more indispensable.MethodsDesign and synthesis of isatin derivatives as surrogates of SB-239629, a bacterial tyrosine-tRNA synthetases (TyrRS) inhibitor. The newly synthesized compounds were screened for their antimicrobial and antibiofilm activities. Docking studies were used to investigate potential binding modes of these compounds with TyrRS.Results and DiscussionNewly synthesized isatin-decorated thiazole derivatives (7b, 7d, and 14b) have shown potent antimicrobial activities against E. coli, a representative of gram-negative bacteria. Also, 7f showed the best activity against Methicillin Resistant Staphylococcus aureus (MRSA). In addition, 7h and 11f were found to have antifungal activities against Candida albicans equivalent to that of the reference Nystatin. All the new isatin derivatives with antimicrobial activities were found to exhibit strong biofilm distortion effects at half their minimum inhibitory concentrations (MIC). Moreover, thiazole derivatives 11a-f showed promising biofilm formation inhibition. Finally, molecular docking studies were used to investigate possible binding modes of target compounds with S. aureus and E. coli TyrRS.ConclusionThe novel isatin-decorated thiazole derivatives show strong antimicrobial and antifungal activities with potential action on TyrRS.

Synthesis, Characterization and Evaluation of Some Pyranopyrazole Derivatives as Multifunction Additives for Medium Lubricating Oils

The current work involves synthesis of 6-amino-4-(4-hydroxyl-3-methoxyphenyl)-3-methyl-1-phenyl-1,4- dihydropyrano[2,3-c]pyrazole-5-carbonitrile (2) by condensation of 2-(4-hydroxyl-3-methoxybenzylidine) malononitrile (1) with 3-methyl-1-phenyl-2-pyrazolin-5-one. The product 2 was then reacted with various aldehydes to form a series of Schiff base derivatives 3a-h. The reaction of the chosen Schiff base derivatives (3a and 3b) with mercaptoacetic acid gave thiazolidinone derivatives (4a and 4b). The structures of prepared compounds were confirmed using FT-IR, 1H NMR, and 13C NMR spectroscopies. They were evaluated as good copper corrosion inhibitors, anti-rust, and antioxidants. This was done by mixing them with the base medium lubricating oil (type 60 stock) provided by the Iraqi Midland Refineries Company/Al-Daura according to the American Society of Testing and Materials ASTM-D130, ASTM-D665, and Institute of Petroleum's testing method, oxidation stability test (IP-280), respectively.

Halogenated Flavonoid Derivatives Display Antiangiogenic Activity.

Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40–55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4−C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target’s binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.

Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents

Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

Green solvent-free synthesis of new N-heterocycle-L-ascorbic acid hybrids and their antiproliferative evaluation.

Aim: The authors' aim was to improve the application of copper-catalyzed azide-alkyne cycloaddition in the synthesis of hybrids containing biologically significant nucleobases and L-ascorbic acid scaffolds by introducing an environmentally friendly and waste-free ball mill. Results: Two series of hybrids with a purine, pyrrolo[2,3-d]pyrimidine or 5-substituted pyrimidine attached to 2,3-dibenzyl-L-ascorbic acid via a hydroxyethyl- (15a-23a) or ethylidene-1,2,3-triazolyl (15b-23b) bridge were prepared by ball milling and conventional synthesis. The unsaturated 6-chloroadenine L-ascorbic acid derivative 16b can be highlighted as a lead compound and showed strong antiproliferative activity against HepG2 (hepatocellular carcinoma) and SW620 (colorectal adenocarcinoma) cells. Conclusion: Mechanochemical synthesis was superior in terms of sustainability, reaction rate and yield, highlighting the advantageous applications of ball milling over classical reactions.

Synthesis of Sulfur-Containing Analogues of Hedychenone, a Labdane Diterpenoid from Hedychium spicatum.

The labdane diterpene hedychenone, isolated from Hedychium spicatum, is an example of a furan-containing natural product. Herein, a new and efficient method for the synthesis of 19 new thio analogues of hedychenone is reported. The present methodology exhibits a broad substrate scope with good to excellent yields without metal or base under mild reaction conditions. The natural compound 1 and four semisynthetic derivatives (3a, 3b, 3i, and 3j) exhibited strong α-glucosidase inhibition activity with IC50 values of 15.93 ± 0.29, 9.70 ± 0.33, 11.82 ± 0.06, 12.23 ± 0.33, and 12.15 ± 0.14 μg/mL, respectively. In addition, compound 3e (6.0 ± 0.04 mm; zone of inhibition) displayed antibacterial activity against Staphylococcus aureus. This study increases the chemical diversity of bioactive hedychenone derivatives and provides a direction for the development of antidiabetic agents.

Novel 2-Nitroimidazole and Imidazooxazole Derivatives and their Activity against Trypanosoma cruzi and Mycobacterium tuberculosis.

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. 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). 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 β-galactosidase-transfected Tulahuen strain. Their antimycobacterial activity was evaluated against Mtb strain H37Rv. 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. 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.

Ruthenium and iridium complexes bearing porphyrin moieties: PDT efficacy against resistant melanoma cells

Porphyrin derivatives present an excellent ability to act as photosensitizers (PS) in photodynamic therapy (PDT). Ruthenium and iridium complexes, mainly containing pyridine ligands, also have been highlighted as potential PS for PDT, due to their photochemical and photophysical properties. The combination of porphyrin derivatives with iridium or ruthenium ions may create singular features and, consequently, improve the PDT effect. In this paper, we report the synthesis, characterization and efficacy of porphyrin derivatives bearing attached ruthenium or iridium terpyridine units to act as PS against resistant melanoma cells (B16F10 cell model). The choice of the porphyrin derivatives to carry out this study was related with their efficacy to generate reactive oxygen species (ROS), the presence of anchoring groups to enable the coordination with ruthenium and iridium metal ions and on the studies of subcellular localization. In the PDT studies, a cell viability decrease was observed in the presence of compounds 4a (ruthenium derivative) and 3b (iridium derivative) at lower concentrations due to the high values of singlet oxygen quantum yield and cellular uptake found. The fluorescence of derivative 3b was observed uniformly dispersed by the cells.