Thiazole Ring—A Biologically Active Scaffold

Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. Objective: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. Results: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.     

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.     

Microsolvation effects on the excited-state dynamics of protonated tryptophan

To better understand the complex photophysics of the amino acid tryptophan, which is widely used as a probe of protein structure and dynamics, we have measured electronic spectra of protonated, gas-phase tryptophan solvated with a controlled number of water molecules and cooled to approximately 10 K. We observe that, even at this temperature, the bare molecule exhibits a broad electronic spectrum, implying ultrafast, nonradiative decay of the excited state. Surprisingly, the addition of two water molecules sufficiently lengthens the excited-state lifetime that we obtain a fully vibrationally resolved electronic spectrum. Quantum chemical calculations at the RI-CC2/aug-cc-pVDZ level, together with TDDFT/pw based first-principles MD simulations of the excited-state dynamics, clearly demonstrate how interactions with water destabilize the photodissociative states and increase the excited-state lifetime.     

Synthesis,Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives

Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2^® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.     

From By-Products to Fertilizer: Chemical Characterization Using UPLC-QToF-MS via Suspect and Non-Target Screening Strategies

The increasing demands of agriculture and the food market have resulted in intensive agricultural practices using synthetic fertilizers to maximize production. However, significant efforts have been made to implement more environmentally friendly procedures, such as composting, to overcome the adverse impact of these invasive practices. In the terms of this research, composting was applied to the production of two biofertilizers, using onion and mushroom by-products as raw materials respectively. The main purposes of this work were to identify the compounds that pass from the raw materials to the final products (onion-based and mushroom-based), as well as the characterization of the chemical profile of these final products following suspect and non-target screening workflows via UPLC-qToF-MS. Overall, 14 common compounds were identified in the onion and its final product, while 12 compounds were found in the mushroom and its corresponding product. These compounds belong to fatty acids, organic acids, and flavonoids, which could be beneficial to plant health. The determination of parameters, such as the pH, conductivity, organic matter, nitrogen content, and elemental analysis, were conducted for the overall characterization of the aforementioned products.     

Chromenol Derivatives as Novel Antifungal Agents: Synthesis,In Silico and In Vitro Evaluation

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.     

Infrared spectroscopy of hydrated amino acids in the gas phase: protonated and lithiated valine

We report here infrared spectra of protonated and lithiated valine with varying degrees of hydration in the gas phase and interpret them with the help of DFT calculations at the B3LYP/6-31++G** level. In both the protonated and lithiated species our results clearly indicate that the solvation process is driven first by solvation of the charge site and subsequently by formation of a second solvation shell. The infrared spectra of Val x Li+ (H2O)4 and Val x H+ (H2O)4 are strikingly similar in the region of the spectrum corresponding to hydrogen-bonded stretches of donor water molecules, suggesting that in both cases similar extended water structures are formed once the charge site is solvated. In the case of the lithiated species, our spectra are consistent with a conformation change of the amino acid backbone from syn to anti accompanied by a change in the lithium binding from a NO coordination to OO coordination configuration upon addition of the third water molecule. This change in the mode of metal ion binding was also observed previously by Williams and Lemoff [J. Am. Soc. Mass Spectrom. 2004, 15, 1014-1024] using blackbody infrared radiative dissociation (BIRD). In contrast to the zwitterion formation inferred from results of the BIRD experiments upon addition of a third water molecule, our spectra, which are a more direct probe of structure, show no evidence for zwitterion formation with the addition of up to four water molecules.     

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation

Background: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance of microbes to existing drugs creates the need for the development of new effective antimicrobial agents. In an attempt to improve the antibacterial activity of previously synthesized compounds modifications to their structures were performed. Methods: Nineteen thiazolidinone derivatives with 6-Cl, 4-OMe, 6-CN, 6-adamantan, 4-Me, 6-adamantan substituents at benzothiazole ring were synthesized and evaluated against panel of four bacterial strains S. aureus, L. monocytogenes, E. coli and S. typhimirium and three resistant strains MRSA, E. coli and P. aeruginosa in order to improve activity of previously evaluated 6-OCF₃-benzothiazole-based thiazolidinones. The evaluation of minimum inhibitory and minimum bactericidal concentration was determined by microdilution method. As reference compounds ampicillin and streptomycin were used. Results: All compounds showed antibacterial activity with MIC in range of 0.12–0.75 mg/mL and MBC at 0.25–>1.00 mg/mL The most active compound among all tested appeared to be compound 18, with MIC at 0.10 mg/mL and MBC at 0.12 mg/mL against P. aeruginosa. as well as against resistant strain P. aeruginosa with MIC at 0.06 mg/mL and MBC at 0.12 mg/mL almost equipotent with streptomycin and better than ampicillin. Docking studies predicted that the inhibition of LD-carboxypeptidase is probably the possible mechanism of antibacterial activity of tested compounds. Conclusion: The best improvement of antibacterial activity after modifications was achieved by replacement of 6-OCF₃ substituent in benzothiazole moiety by 6-Cl against S. aureus, MRSA and resistant strain of E. coli by 2.5 folds, while against L. monocytogenes and S. typhimirium from 4 to 5 folds.     

Cut-off analysis of coherent vortical structure identification in a three-dimensional external flow

Vortical structure identification has more recently been applied in the study of the transport of vortical structures in low Reynolds number three-dimensional complex geometry flows. An important issue in this identification procedure is to choose an appropriate cut-off value ${\lambda }_2$ which takes into consideration the finite precision vortex interfaces. This cut-off choice is studied in this Note and applied to an external flow around a curved cylinder. The vortex identification technique at different cut-off values is compared to the threshold of the vorticity field showing the efficiency of choosing the optimal tolerance gap. The computations are performed with a fully three-dimensional spectral/hp element method. To cite this article: A. Miliou et al., C. R. Mecanique 333 (2005).