Sustainable Synthesis of Novel Hydroxylated Tranilast Analogues and Their Bioactivities

 Molecules 2026, 31(8), 1340; https://doi.org/10.3390/molecules31081340

Abstract

Tranilast, an anti-allergic drug with well-established anti-inflammatory, antifibrotic, and antiproliferative properties, suffers from poor water solubility and low bioavailability, which limit its therapeutic potential. To improve its pharmacological profile, we designed and synthesized a novel series of hydroxylated Tranilast analogues. The compounds were obtained through a green, single-step coupling reaction between activated methoxy-substituted hydroxycinnamic acids and anthranilic or hydroxyanthranilic acids, using a triethylamine–isobutyl chloroformate system in environmentally friendly solvents. Fifteen derivatives were isolated in good to excellent yields (63–94%) without chromatographic purification. The synthesized compounds were evaluated for antimicrobial, antioxidant, anti-inflammatory, and antiproliferative activities. Several analogues displayed notable antimicrobial effects against Candida albicans, Staphylococcus aureus, and Klebsiella pneumoniae, with minimum inhibitory concentrations as low as 75 µg/mL. Hydroxylated derivatives showed enhanced radical-scavenging activity in DPPH and ABTS assays compared with Tranilast. Selected compounds also demonstrated suggestive antiproliferative effects against LNCaP prostate cancer cells while maintaining low cytotoxicity toward HaCaT keratinocytes, indicating favourable selectivity. Furthermore, some derivatives significantly reduced nitric oxide production in LPS-stimulated HaCaT cells, confirming their anti-inflammatory potential. Overall, hydroxylation proves to be an effective strategy for improving the biological profile of Tranilast, yielding promising candidates for further pharmacological development.

Keywords: cinnamides; structure–activity relationship; anti-inflammatory; antimicrobial; antiproliferative activity

Eco-Friendly Synthesis of 2-Styryl-benzo[d][1,3]oxazin-4-ones from N-Cinnamoyl-Anthranilic Acids

Molecules 2026, 31, 709

https://doi.org/10.3390/molecules31040709

Abstract:

N-cinnamoyl anthranilic acids are synthesized in a single, eco-friendly step by condensing

various cinnamic acids with free 2-aminobenzoic acid derivatives using the mixed carbonic

anhydride method. Subsequently, converting the resulting N-cinnamoyl anthranilic acids

into their corresponding mixed carbonic anhydrides rapidly and efficiently affords 2-styryl-

benzo[d][1,3]oxazin-4-ones. The method employs green solvents, such as acetone and

2-methyltetrahydrofuran; does not require metal catalysts or reflux conditions; and yields

the desired final products without chromatographic purification.

Keywords: benzo[d][1,3] oxazin-4-ones; anthranilic acids; hydroxycinnamic acids

Antifungal and Antibiofilm Activities of 2-Aminobenzoic Acid Derivatives Against a Clinical Ocular Candida albicans Isolate for Biomedical Applications

Abstract: 

Ocular fungal infections are slow-progressing conditions that primarily affect the cornea but can also involve the entire eyeball. Candida albicans is one of the most involved species. Both diagnosing and treating these infections require prompt and effective action. However, the currently available treatment options mainly rely on azoles and polyenes, which are known for their poor penetration into ocular tissue and associated toxicity. Moreover, conventional antifungals are usually ineffective when tested against biofilm-associated infections, mainly due to the metabolically inactive state of dormant cells embedded in the extracellular biofilm matrix. Here, analysis of the in vitro antifungal activity of four 2-aminobenzoic acid derivatives synthesized using a green method and their combination with Fluconazole (FLC) showed efficacy against the FLC-resistant clinical isolate of C. albicans under both planktonic and biofilm formation conditions. Results showed that compounds 1 and 2 exhibited the best antifungal activity in the checkerboard association test, presenting a synergistic effect towards antifungal action. The downregulation of HWP, ERG11, and ASL3 genes during biofilm inhibition suggested a reduced capacity of the four compounds for hyphal growth and adhesion, as well as a decrease in pathogenicity due to the downregulation of some SAP genes. In vitro and in vivo toxicity profiles indicated that these compounds exhibited low toxicity, as well as the absence of genotoxic effects. Therefore, green-synthesized 2-aminobenzoic acid derivatives may have potential as antifungal agents for the inhibition of C. albicans growth and biofilm formation.

Keywords: antibiofilm; antimicrobials; Candida albicans; 2-aminobenzoic acid derivatives; gene expression

Antibiotics 2025, 14, 432. 

https://doi.org/10.3390/antibiotics14050

Improved Chemical Synthesis of Avenanthramides Family and its Analogs by Mixed Anhydride Method

Abstract

Amides derived from common hydroxycinnamic acids — including 4-hydroxycinnamic acid, 3-methoxy-4-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxycinnamic acid, and 3,4,5-trimethoxycinnamic acid — along with various free aminobenzoic acids, such as 5-hydroxy-2-aminobenzoic acid, a key component of the avenanthramide family, have been rapidly synthesized using an innovative, environmentally friendly synthetic methodology. This approach, grounded in traditional chemistry, utilizes mixed anhydrides to simultaneously protect and activate hydroxycinnamic acids through the actions of triethylamine and isobutyl chloroformate while employing acetone as a green solvent. The resulting amides, formed from the coupling with free aromatic amino acids, are constructed as O-carbonate-protected derivatives with high yields and purity, isolated directly via crystallization, thus eliminating chromatographic or HPLC purifications. Furthermore, free phenols can be conveniently released on demand using morpholine in methanol. Under these conditions, C-protected aromatic amino acids remain unacylated. This synthetic strategy represents a significant advancement over conventional acyl chloride methodologies, which often rely on toxic reagents and solvents and entail time-consuming and complex procedures. It enhances the production of important phytochemicals such as Avenanthramides and opens doors to various analogs, paving the way for potential pharmacological applications.

Research Article

Open Access

Armando Zarrelli, Luigi Longobardo

First published: 16 April 2025

 

https://doi.org/10.1002/ejoc.202500169

Sustainable Chemical Derivatization of Hydroxycinnamic Acids

Graphical Abstract

Hydroxycinnamic acids have been derivatized in ethyl acetate using N-methyl morpholine and an alkyl chloroformate to protect and activate them. Amines were added to produce O-carbonate-protected amides, and DMAP was used as a catalyst to add alcohols, resulting in protected esters. The related acylated derivatives were obtained by activating the compounds in acetone and adding nucleophiles in water, such as free amino acids, sodium azide, or sodium hydroxide.

Abstract

Green solvents like ethyl acetate and acetone convert hydroxycinnamic acids into natural and unnatural derivatives such as amides, esters, and other valuable synthetic intermediates. Employing as protection-activation a system based on an alkyl chloroformate and N-methyl morpholine, ethyl acetate emerges as an excellent solvent for coupling O-carbonate-protected mixed anhydrides in acylation reactions of C-protected amino acids, amines, and catalyzed acylation of alcohols. This results in high yields of O-protected phenolic amides and esters. Acetone is preferred for acyl nucleophilic substitution reactions involving ionic species like free amino acids, sodium azide, and sodium hydroxide, all added in water. This approach releases the resultant O-protected acylation products. Free phenolic compounds are promptly obtained on demand through carbonate deprotection. This synthetic method offers a simplified procedure and employs low-cost reagents to prepare natural and unnatural hydroxycinnamic acid derivatives.

Dr. Luigi Longobardo, Prof. Giovanni Di Fabio, Prof. Armando Zarrelli

First published: 13 March 2024

 

https://doi.org/10.1002/slct.202305046

Research Activities

Hydroxycinnamic amides and N-Hydroxycinnamoyl-amino acids

doi.org/10.1002/slct.202000176

z Sustainable Chemistry Protection and Activation of Hydroxycinnamic Acids in Water Marina DellaGreca and Luigi Longobardo*[a] Hydroxycinnamic acids such as p-coumaric, ferulic, sinapic and caffeic acids were protected as carbonates and activated as mixed carbonic anhydrides in water at RT by adding a base and isobutyl chloroformate. These anhydrides were used for amine and C-protected α-amino acid acylation to give O-carbonate protected phenolic amides. Acylation of free α-amino acids was performed in acetone-water in high yields producing the O- carbonate protected N-hydroxycinnamoyl-α-amino acids. Pure derivatives were obtained in many cases directly by crystallization. Free phenolic compounds were rapidly obtained by carbonate deprotection with piperidine. The method offers a novel route for amide bond formation in water and the direct functionalization of hydroxycinnamic acid families with free α- amino acids, providing a facile preparation of precious natural bioactive derivatives. Department of Chemical Science University of Napoli Federico II Via Cinthia 4 - 80126 Napoli - Italy E-mail: luilongo@unina.it Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.202000176 ChemistrySelect 2020, 5, 4588 – 4591

Hydroxycinnamyl Alcohols

A Facile Preparation of Hydroxycinnamyl Alcohols with Simultaneous Protection of Phenol Groups as Carbonate

Lucia Panzella, Marina DellaGreca, and Luigi Longobardo*[a]

A novel procedure for reduction and simultaneous protection of phenol groups of hydroxycinnamic acids to the related alcohols has been developed. During the formation of mixed anhydrides from the acids and an alkyl chloroformate, the phenol was protected as carbonate, and the mixed anhydrides were reduced with an aqueous solution of sodium borohydride. Free phenols were obtained by deprotection under mild conditions with 30% aq. NH4OH in methanol. O-protected phenolic alcohols can be converted by standard methods into orthogonally protected derivatives. This rapid and efficient synthetic method offers a simple and high-yield preparation of these important fine chemicals, overcoming the tedious and costly procedures associate with the use of strong reducing agents such as LiAlH4 and DIBALH.

ChemistrySelect 2018, 3, 10637 –10640

 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Novel thiol- and thioether-containing amino acids: cystathionine and homocysteine families

Abstract 

Natural L-homocysteine and L,L-cystathionine, along with a series of unnatural analogues, have been prepared from L-aspartic and L-glutamic acid. Manipulation of the protected derivatives provided x-iodoamino acids, which were used in thioalkylation reactions of sulfur nucleophiles, such as the ester of L-cysteine and potassium thioacetate.

A practical route to β2,3-amino acids with alkyl side chains

Longobardo et al. SpringerPlus (2015) 4:553DOI 10.1186/s40064-015-1351-6
RESEARCH
A practical route to β2,3-amino acids with alkyl side chains

Luigi Longobardo1*, Marina DellaGreca1 and Ivan de Paola2

*Correspondence: luilongo@unina.it1 Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, Via Cinthia 4, 80126 Naples, Italy

Full list of author information is available at the end of the articleOp



Abstract

en Access

Enantiopure N(Boc)-β3-amino nitriles, valuable synthetic intermediates in the multistep homologation of α-amino acids, were alkylated using n-BuLi as base. 

Alkylations afforded easily separable, almost equimolecular mixtures of diastereomeric N(Boc)-protected syn and anti β2,3-amino nitriles. 

Suitable manipulations of both cyano and amino groups eventually led to enantiopure N- and/or C-protected β2,3-amino acids. 

For example, methanolysis using conc. HCl gas in MeOH, provides C-protected β2,3 amino acids in excellent yields. 
This methodology is applied to the synthesis of a series N(Boc)-β2,3-dialkyl amino nitriles derived from L-phenylalanine, D-phenylalanine, L-valine and one C-protected β2,3 amino acid. 

We demonstrate an efficient procedure for the preparation of anti and syn β2,3-amino acids with alkyl side chains, from α-amino acids in reasonable yields.

Keywords: Beta-amino acids, Beta-amino nitriles, Alkylation, Homologation, Carbanions

Esami CHIMICA ORGANICA BPM 2013

I prossimi appelli della sessione estiva 2013 per sostenere gli esami di Chimica Organica  per BIOLOGIA DELLE PRODUZIONI MARINE
si svolgeranno:

• Mercoledì 12 giugno 2013 alle ore 10 a MSA
• Mercoledi 17 luglio 2013 alle ore 10 a MSA

Inviare una e-mail di prenotazione a: luilongo@gmail.com

Immaginarie fasce della docenza universitaria

Sulle Immaginarie Fasce della Docenza Universitaria

Abstract: This report concern on unreality of teaching level in italian university. The simple analysis of a real case show that the rules applied for teaching assignments are based on pure imaginary considerations, and are quite distant from real experimental data. These rules indirectly generate resources dissipation, associated with a low quality of teaching activity. 

L’attuale sistema di reclutamento dei professori universitari, secondo quanto stabilito dai regolamenti ANVUR, è basato quasi esclusivamente su degli indicatori che misurano la presunta qualità e quantita della produzione scientifica dei singoli candidati, ma curiosamente non fa alcun riferimento a precedenti esperienze di insegnamento maturate dai candidati.

E’ come si cercasse un autista di autobus, ma non gli viene chiesto se ha la patente. Questa ulteriore, fastidiosa condizione dovrebbe essere accertata piuttosto da una commissione locale. E’ un impianto basato sulla convinzione che chi fa una buona ricerca, di per sé  abbia anche il talento di offrire buone prestazioni didattiche.  

Certo si è verificato molte volte nelle aule universitarie, come molti di noi ricordano con vero piacere, ma sono delle notabili eccezioni, non la norma. Fare una buona ricerca significa soprattutto studiare il lavoro degli altri, avere una delicata relazione con gli apparati sperimentali e con le sostanze che si manipolano. Con questi attrezzi ci si può misurare con la realtà delle entità materiali oggetto di studio, cioè si possono organizzare degli esperimenti nei quali si interroga il mondo reale. Le risposte ottenute molto spesso non soddisfano completamente le nostre curiosità, ma aprono nuovi e insospettabili scenari, che spingono a pensare a nuovi esperimenti.

Fare una buona didattica significa tutta una altra cosa, significa in primo luogo non fornire agli studenti banalmente una massa di nozioni, ma entrare direttamente nella loro testa, insegnando loro soprattutto a ragionare su come usare correttamente le nozioni acquisite. 

Mi sembrano in effetti due attività abbastanza diverse, l’una concernente i colleghi, i libri, le tecnologia e le molecole, l’altra solo il cervello di tanti giovani umani. E’ chiaro che essere dei buoni ricercatori non implica automaticamente essere anche dei buoni docenti. Una delicata relazione con gli apparati sperimentali non è sufficiente ad avere una corretta relazione con giovani umani. Essere dei buoni docenti significa infine essere necessariamente anche dei buoni ricercatori, perché bisogna fornire agli studenti nozioni "aggiornate".

Dunque, non sarebbe necessario soprattutto valutare le capacità didattiche dei candidati, che di solito hanno molti anni di attività di insegnamento alle spalle?  E’ un mistero.

Ma a pensarci bene, cosa rappresentano le tre fasce della docenza universitaria F1, F2 e F3 che plasmano la vita dei nostri atenei?

La dimostrazione che la legge F1 > F2 > F3 , che definisce prestazioni e retribuzioni delle fasce della docenza, è falsa, è molto semplice.

Qualunque legge, infatti, o è vera o è falsa. Non può essere entrambe le cose.

Per verificare se una legge è vera o è falsa bisogna fare degli esperimenti. Cioè bisogna calare la legge nella realtà. In questo modo si ottengono dei dati sperimentali, dei numeri, che ci dicono se la legge è vera o è falsa. 

Calando la  F1 > F2 > F3 nelle aule universitarie, si ottengono i seguenti set di dati sperimentali:

  A.   F1 > F2 > F3 

 B-     F1 > F3 > F2 

 C-     F2 > F1 > F3 

 D-    F2 > F3 > F1 

 E-     F3 > F1 > F2 

 F-     F3 > F2 > F1 

I dati ci dicono che effettivamente il caso A esiste nella realtà, ma esistono anche tutti gli altri casi. 

La quantificazione dei casi è ovviamente possibile solo conoscendo il peso relativo di ciascun caso, ma occorrerebbe conoscere le valutazioni della didattica, in tutte le realtà in cui essa viene svolta. 

Il risultato non potrebbe che dimostrare che la legge è falsa, cioè nella realtà la legge è sbagliata. In verità per dimostrarlo basta anche un solo caso compreso tra B e F.

La legge A.  F1 > F2 > F3  rimane valida nelle casse degli uffici stipendi.