Background/Objectives: Biofilm-related infections represent a major concern in clinical practice because of their poor responsiveness to standard antimicrobial treatments. Over the past decade, many efforts have been made to identify new compounds capable of inhibiting this particularly resistant form of bacterial life. Although several compounds have shown interesting anti-biofilm properties, none have reached the clinic. Methods: In the present work, we describe the synthesis and biological assessment as anti-biofilm agents, of a novel library of twenty-one imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines. Results: The newly synthesized compounds were in vitro evaluated for their ability to prevent biofilm formation and to eradicate established biofilms in Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 15442. Additionally, the most potent compounds, 9g and 9u, were in vivo assayed for their safety profile and the anti-infective effect in a Galleria mellonella model. Conclusions: Derivatives 9g, 9i, 9n, 9q and 9u proved to be potent inhibitors of S. aureus biofilm showing BIC50 values lower than 15 µg/mL. Noteworthy, the in vivo results revealed the promising protective properties of compound 9u in the early stage of staphylococcal infection.

The endocannabinoid system is implicated in multiple physiological and pathological processes, making it a promising target for therapeutic intervention. CB1 receptor antagonists have shown potential in treating metabolic, neuropsychiatric, and addiction-related disorders. However, the adverse effects of CB1 antagonists like rimonabant have spurred the development of new compounds with improved safety profiles. This study investigates the pharmacological effects of a novel synthetic compound, 3-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-2-phenylchinazolin-4(3H)-one (QD13), a quinazolinone derivative designed to antagonize CB1 receptor activity selectively. Molecular docking studies were conducted to assess the binding affinity of QD13 at the CB1 receptor, comparing it to the reference antagonist AM6538. The effects of QD13 were evaluated using the tetrad task in C57Bl/6 mice. The ability of QD13 to antagonize the effects of the CB1 agonist CP55,940 on locomotor activity, body temperature, catalepsy, and nociception were measured. Additionally, isolated ileum preparations were used to determine QD13's impact in counteracting the effects of CB1 agonists on gastrointestinal contractility. Docking analysis confirmed QD13's occupation of the CB1 receptor binding site, overlapping with AM6538, suggesting strong affinity. QD13 dose-dependently reversed CP55,940-induced hypomotility, catalepsy, analgesia, and hypothermia, with significant effects observed at 1 mg/kg and 3 mg/kg. Moreover, QD13 counteracted CP55,940-induced inhibition of ileal contractility, supporting its antagonistic activity in peripheral tissues. QD13 shows promising CB1 receptor antagonistic activity both centrally and peripherally. Its modulation of CB1 effects in the tetrad task and gastrointestinal assays suggests potential therapy for neuropsychiatric disorders, obesity, and addiction. Further studies are needed to clarify QD13's safety and efficacy.

Several new synthesized 4-cinnamamido- and 2-phenoxyacedamido-1H-pyrazol-5-yl)benzamides were obtained by two multi step different synthetic routes in order to maximize their yield. The new derivatives were screened to determinate the antiproliferative, antimicrobial and antibiofilm activity. The biological results showed how, respect to the antiproliferative and antimicrobial activities, the compounds showed a low to missing activity. Different are the results obtained with respect to the antibiofilm activity, especially towards Candida albicans. Most of the synthesized compounds showed a good percentage inhibition of biofilm formation ranging from 60 to 73% with a Biofilm Inhibition Concentration 50% (BIC50) from 0.13 to 0.01 µM. Among the synthesized the ethyl 5-(4-(2-(4-chlorophenoxy)acetamido)benzamido)-1-methyl-1H-pyrazole-4-carboxylate (27c) resulted the most active with a BIC50 of 0.01 µM. According to the result obtained, such compound could be considered a lead subject of further studies to obtain novel and more effective antibiofilm agents against C. albicans infections.

Background:Occupational hazards believed to cause musculoskeletal disorders in rope workers are traditionally associated with maintaining incongruous postures for prolonged periods of time. Design and methods:A cross-sectional survey was conducted on 132 technical operators in the wind energy and acrobatic construction sectors, who work on ropes, analysing the ergonomic characteristics of the environments, the way in which tasks are carried out, the strain perceived by individual workers, and assessing the presence of any musculoskeletal disorders (MSDs) by means of an objective examination focused on the anatomical districts that were the object of our study. Results:Analysis of the data obtained showed that there were differences in the perception of the level of physical intensity and perceived exertion between the groups of workers. Statistical analysis also revealed a significant association between the frequency of MSDs analysed and perceived exertion. Discussion:The most significant finding to emerge from this study is the high prevalence of MSDs of the cervical spine (52.94%), the upper limbs (29.41%), and the dorso-lumbar spine (17.65%). These values differ from those classically found in those exposed to the risk of conventional manual handling of loads. Conclusions:The high prevalence of disorders of the cervical spine, the scapulo-humeral girdle and the upper limbs, indicates the need to consider the forced position to be assumed for a large part of the work activity, staticity, and the inability to move the lower limbs for long periods as the predominant risk in rope work.

Helianthemum lippii is a perennial shrubby plant growing in the sandy environments of Italy, Mediterranean countries of North Africa and Middle East. H. lippii is used in traditional medicine but there are very few reports referring to the phytochemical characterization, the ethnopharmacology, and the biological activity of H. lippii. The goal of this study was to determine the phytochemical composition of different H. lippii extracts, cold (CME) and hot (HME) methanol, cold (CPEE) and hot (HPEE) petroleum ether, as well as to evaluate their anticancer and antimicrobial activities and biofilm formation reduction. Fifty-fours phytocompounds have been determined by HPLC-UV-ESI-QTOF-MS analysis. All the four extracts reduced the viability of human MDA-MB231 and HCT116 cells, being cold and hot methanol extracts the most effective. The antimicrobial activity against S. aureus, P. aeruginosa, E. faecalis, E. coli, C. albicans was also evaluated. Data showed the greater susceptibility of S. aureus to hot methanolic extract. Concerning antifungal activity, C. albicans resulted more susceptible to petroleum ether. Moreover, some of the samples exhibited a good antibiofilm activity both on immature and on mature biofilms. The four extracts showed interesting antimicrobial and cytotoxic activities and can be considered good candidates for new therapeutic applications

Artemisia arborescens (Vaill.) L. is a perennial shrubby plant growing along the coastal strips of the Mediterranean region. It is used in traditional medicine. Its essential oil and solvent extracts exhibit a very interesting chemotherapeutic potential, which makes this plant useful in maintaining human health. The goal of this study was to determine the phytochemical composition of the petroleum ether and methanol extracts, as well as to evaluate anticancer activities and antimicrobial and biofilm formation reduction. Thirty-nine phytochemical compounds in negative ion mode and 25 in positive ion mode were identified by HPLC-ESI-QTOF-MS. All four extracts reduced the viability of human MDA-MB231 and HCT116 cancer cells suggesting a similar cytotoxic efficacy of the different extracts in MDA-MB231 and more pronounced antiproliferative effects on HCT116 cells treated with HPEE and CPEE. Antimicrobial activity was exhibited by the hot petroleum ether extract against all tested bacteria (MIC 0.15-2.5 mg/mL), except for S. agalactiae. Both methanol extracts showed activity against C. albicans with a MIC value of 2.5 mg/mL, and a lack of antibacterial activity. To whom concern the anti-biofilm activity, hot methanol extract shows the highest activity in inhibiting biofilm formation among all extract.

Endocannabinoid receptors type 1 and 2 can be managed by pharmacological compounds to regulate different neuronal processes. Hyperactivity or dysfunction in the endocannabinoid system might be implicated in disturbance or abnormality of neural processes, evidencing its relevance for several pathologies. The reported study shows that a new structural analogue of rimonabant, (E)-6-chloro-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-2-styrylquinazolin-4(3H)-one (1), is able to counteract the behavioral signs of the activation of the endocannabinoidergic system induced by the administration of the agonist CP 55,940. The analogue of rimonabant (1) is characterized by a quinazolinone structure bearing a heterocyclic pyrazole nucleus. Behavioral assessment was carried out by tetrad task and the novel object recognition tested on rats, to evaluate cannabinoid effects on declarative memory. The endocannabinidergic system was activated by the administration of the cannabinoid agonist CP 55,940. Our study shows that compound 1 at the dose of 10 mg/kg, 30 min before CP 55,940 administration, is able to counteract the effects exerted by CP 55,940, as shown by an increase in body temperature, in total distance travelled, in latency to fall down and a decrease in tail flick latency. Furthermore, the memory impairment induced by the cannabinoid agonist is prevented by compound 1 showing that it is able to counteract the cannabinoid activation induced by the agonist CP 55,940. Further investigations are in progress to evaluate the pharmacological profile of compound 1 and consider it as a potential candidate for clinical studies and as pharmacological agent in managing different pathological conditions as motor incoordination, obesity, and brain related disorders

The quinazolinone nucleus represents, among the class of fused heterocycles, a very important scaffold to obtain molecules with biological activities. A review of literature revealed how such kind of fused heterocycles, coming from natural or synthetic source, are associated with a wide range of biological activities. This review is mainly directed towards the 4-(3H)-quinazolinones N-3 substituted with a five membered heterocycle in which all the possible combinations of nitrogen, sulfur and oxygen atoms are present.

Polycyclic or O-glycoconiugate polycyclic compounds 1a-g were previously tested for their in vitro antiproliferative activity. In this series of compounds, activity increases as log P decreases. Specifically, compounds 1d and 1g showed lower log P values together with the best antiproliferative profiles. With the aim of extending our understanding of the structure-activity relationship (SAR) of this class of compounds, we prepared new polycyclic derivatives 2a-c, which bear on each of the two phenyl rings hydrophilic substituents (OH, SO2NH2 or NHCOCH3). These substituents are able to form hydrogen bonds and to decrease the partition coefficient value as compared with compound 1d. Compound 2a was slightly more active than 1d, while 2b and 2c had antiproliferative activity comparable to that of 1d. Finally, the role of the two phenyl groups of polycycle derivatives 1 was also investigated. The analog 3, which bears two methyls instead of the two phenyls had a lower log P value (2.94 +/- 1.22) than all the other compounds, but it had negligible antiproliferative activity at 10 mu M. The analysis of the most active derivative 2a revealed a significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB231. After a 24 h treatment, an autophagic process was activated, as demonstrated by an increase in monodansylcadaverine-positive cells as well as by the appearance of the autophagic markers Beclin and LC3II. Prolonging the treatment to 48 h, 2a caused cytotoxicity through the activation of caspase-dependent apoptosis.

Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIPL and caspase-8 activation.

Background Compounds acting on endocannabinoid system regulate different neuronal processes through the cannabinoid receptors activation. The main aim of this study was determining whether the 2-styrylquinazolin-4(3H)-one 5, a structural analogue of rimonabant, was able to counteract the behavioural signs of the activation of the endocannabinoidergic system induced by CP 55.940. Methods Behavioural assessment was carried out using the tetrad task and the novel object recognition test. The endocannabinoidergic system activation was possible by the administration of CP 55.940 and 30 min after rats were tested in the tetrad task for the evaluation of the antinociceptive-, cataleptic-, hypothermic- and locomotor- effects. The evaluation of the declarative memory was carried out through the novel object recognition test. The administration of the new compound was made at three different doses, 30 min before CP 55.940 administration on a separate group of animals. Results Our results demonstrated that compound 5, at the highest dose, was able to counteract the effects exerted by CP 55.940, shown by an increase in body temperature, total distance travelled, latency to fall and decrease in tail flick latency, interfering conjointly in memory impairment. Conclusion This study shows that compound 5 is able to counteract the cannabinoid activation induced by the agonist CP 55.940. Further investigations on its pharmacological profile are mandatory before considering it as a potential candidate for clinical studies and its possible employment as pharmacological agent for the management of different pathological conditions such as motor incoordination, obesity and brain related disorders.

Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1'-biphenyl-4-carboxamides 14a-f and 1,1'-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1'-biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562 cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses performed to explore 17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequent to DNA lesions as demonstrated by the increase in phospho-ATM and γH2AX, two known markers of DNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK and induction of caspase-3 dependent apoptosis.

This paper describes aspects of the chemistry of 4'-substituted spiro[isoindole-1,3'-pyrazoles]. These compounds underwent substitution and/or elimination reactions to afford some new spiro- as well as biaryl derivatives of potential pharmaceutical relevance. Mechanistic considerations are discussed as well.

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.