Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

Sortase A (SrtA) is a membrane enzyme responsible for the covalent anchoring of surface proteins on the cell wall of Gram-positive bacteria. Nowadays it is considered an interesting target for the development of new anti-infective drugs which aim to interfere with important Gram-positive virulence mechanisms. Along the years, we studied the anti-staphylococcal and anti-biofilm activity of some natural and synthetic polyhalogenated pyrrolic compounds, called pyrrolomycins. Some of them were active on Gram-positive pathogens at a μg/mL range of concentration (1.5-0.045 μg/mL) and showed a biofilm inhibition in the range of 50-80%. [1-3] In light of these encouraging results, herein we present our efforts in the design and synthesis of novel pyrrolomycins. To dispose of sufficient amount for the in-depth in vitro investigation, we developed an efficient and easy-to-use microwave synthetic methodology. All compounds showed a good inhibitory activity toward SrtA, in accordance with the molecular modelling studies, having IC50 values ranging from 130 to 300 µM comparable to berberine hydrochloride, our reference compound. Particularly, the pentabromo-derivative exhibited the highest capability to interfere with biofilm formation of S. aureus with an IC50 of 3.4 nM. This compound was also effective in altering S. aureus murein hydrolase activity, responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation. [4

Progettazione e sintesi di nuovi derivati 4-chinazolinonici potenziali inibitori della diidrofolato reduttasi

I chinazolinoni sono composti eterociclici azotati che, insieme alle chinazoline, rappresentano degli importanti farmacofori in possesso di un ampio spettro di proprietà biologiche tra cui quella antitumorale. Recentemente sono stati riportati in letteratura dei derivati 4-chinazolinonici in grado di inibire in vitro l’enzima diidrofolato reduttasi (DHFR) con IC50 comprese tra 0.4 e 1.0 µM [1]. Allo scopo di progettare la sintesi di nuovi potenziali inibitori della DHFR, è stato condotto uno studio di modellistica molecolare considerando tale enzima come biotarget. Tale studio ha portato alla selezione di 42 nuovi derivati 4-chinazolinonici (Figura 1). Attualmente, sono stati sintetizzati 20 dei 42 nuovi derivati 4-chinazolinonici, che sono stati saggiati preliminarmente sulla linea cellulare K562. Il derivato più attivo ha mostrato una IC50 di 18 µM. Sono in corso saggi enzimatici per valutare in vitro l’inibizione dell’enzima DHFR. Bibliografia 1 Al-Omary F.A.M.; et al, Bioorganic & Medicinal Chemistry, 2010, 18, 2849

Sintesi di un isostero del 3,5-dimetil-6-fenil-8-(trifluorometil)-5,6-diidropirazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one (CF3-TZP) con potenziale attività biologica

In un precedente lavoro abbiamo mostrato i risultati relativi alla sintesi ed all’attività biologica del CF3-TZP 1[1] (Figura 1). Le attività antiproliferativa e apoptotica del composto 1 sono state testate su differenti linee cellulari, HL60 sensibili, HL60-R (MDR), K562 e K562-R (resistenti al Gleevec®), mostrando un profilo di attività biologica similare sulle cellule sensibili e resistenti nel range di 21-40 µM per l’IC50 e 36-62 µM per l’AC50. L’analisi citofluorimetrica sulle K562 sensibili ha indicato che il composto 1 determina un arresto dose-dipendente del ciclo cellulare in fase G0-G1 nelle prime 24 h di trattamento, mentre nelle successive 24 h si è notato una riduzione del picco G0-G1 ed un incremento del picco apoptotico subG0-G1. Gli incoraggianti risultati biologici ci hanno spinto a continuare gli studi su questa tipologia di molecole sintetizzando l’isostero 2 (Figura 1) attraverso una lunga via di sintesi (15 steps). Attualmente, sono in corso i saggi biologici per valutare le attività antiproliferativa e apoptotica. Bibliografia 1 Maggio, B.; et al, Eur. J. Med. Chem., 2008, 43, 120

Pirrolomicine che inibiscono la Sortasi A nelle infezioni sostenute da batteri Gram-positivi

La Sortasi A è un enzima di membrana responsabile dell’ancoraggio delle proteine di superficie sulla parete cellulare dei batteri Gram-positivi. Essa è considerata un interessante obiettivo per lo sviluppo di nuovi farmaci anti-infettivi che mirino ad interferire con importanti meccanismi di virulenza Gram-positivi. In un precedente lavoro abbiamo indagato sull’attività antistafilococcica e antibiofilm di alcune Pirrolomicine naturali e sintetiche, composti pirrolici polialogenati attivi su patogeni Gram-positivi, alle concentrazioni di 1.5 e 0.045 µg/mL. I risultati biologici hanno mostrato percentuali di inibizione di biofilm comprese tra 50-80% [1]. Allo scopo di indagare sul loro meccanismo d’azione sono stati condotti studi di modellistica molecolare e saggi di inibizione in vitro sull’enzima Sortasi A (Figura 1). I risultati ottenuti indicano che la Sortasi A potrebbe essere il bersaglio sul quale le Pirrolomicine agiscono, con IC50 comprese tra 130-250 µM, nell’inibizione della formazione di biofilm. Bibliografia 1 Schillaci, D.; et al, Biofouling, 2010, 26, 433

Sigma-1 receptor antagonists: promising players in fighting neuropathic pain

Sigma-1 receptors (S1Rs) are strongly correlated to neuropathic pain (NP), since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effects. In the recent patent landscape, S1R antagonists endowed with nanomolar S1Rs affinity emerged as potent antinociceptive agents. So far, three patented compounds have been proposed for counteracting NP. Particularly PV 752 and AV1066, disclosed by the University of Pavia (Italy) and Anavex, respectively, showed good analgesic activity in preclinical studies. Moreover, E 52862 developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans

Urea-based anticancer agents. Exploring 100-years of research with an eye to the future

Suramin was the first urea-based drug to be approved in clinic, and in the following century a number of milestone drugs based on this scaffold were developed. Indeed, urea soon became a privileged scaffold in medicinal chemistry for its capability to establish a peculiar network of drug-target interactions, for its physicochemical properties that are useful for tuning the druggability of the new chemical entities, and for its structural and synthetic versatility that opened the door to numerous drug design possibilities. In this review, we highlight the relevance of the urea moiety in the medicinal chemistry scenario of anticancer drugs with a special focus on the kinase inhibitors for which this scaffold represented and still represents a pivotal pharmacophoric feature. A general outlook on the approved drugs, recent patents, and current research in this field is herein provided, and the role of the urea moiety in the drug discovery process is discussed form a medicinal chemistry standpoint. We believe that the present review can benefit both academia and pharmaceutical companies' medicinal chemists to prompt research towards new urea derivatives as anticancer agents

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams

Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer

Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles' heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer