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A mild, chemoselective and sustainable biocatalysed synthesis of sulfoxides has been developed exploiting CALB and using AcOEt with a dual role of more environmentally friendly reaction solvent and enzyme substrate. A series of sulfoxides, including the drug omeprazole, have been synthesised in high yields and with excellent E-factors.

Sulfoxides are a class of organic compounds that find wide application in medicinal and organic chemistry. Several biocatalytic approaches have been developed to synthesise enantioenriched sulfoxides, mainly by exploiting oxidative enzymes. Recently, the use of reductive enzymes such as Msr and Dms has emerged as a new, alternative method to obtain enantiopure sulfoxides from racemic mixtures. In parallel, novel oxidative approaches, employing nonclassical solvents such as ionic liquids (ILs) and deep eutectic solvents (DESs), have been developed as greener and more sustainable biocatalytic synthetic pathways. This minireview aims highlights the recent advances made in the biocatalytic synthesis of enantioenriched sulfoxides by employing such unconventional approaches., Going greener: Enantioenriched sulfoxides can be synthesized by exploiting the new reductive enzymes Msr and Dms or using classical oxidative enzymes in the presence of unconventional solvents in a greener and more sustainable way.

Biocatalysis is a branch of catalysis that exploits enzymes to perform highly stereoselective chemical transformations under mild and sustainable conditions. This Synpact highlights how biocatalysis can be used in the synthesis of chiral 1,3-mercaptoalkanols, an important class of compounds responsible for the flavours and aromas of many foods and beverages. The identification of two ketoreductase (KRED) enzymes able to reduce prochiral ketone precursors enantioselectively to 1,3-mercaptoalkanols bearing a C–O stereocentre is presented. In addition, the combination of a photocatalytic thia-Michael reaction to access prochiral ketones with subsequent KRED-biocatalysed reduction in a one-pot cascade is presented. Photo-biocatalysed cascades represent one of the new and most intriguing challenges in synthetic chemistry, because the combination of different catalytic methodologies in domino processes offers unique opportunities to outperform sequential reactions with a high degree of selectivity and the avoidance of the need to isolate reaction intermediates.1 Introduction2 Biocatalytic Synthesis of 1,3-Mercaptoalkanols3 Photo-Biocatalytic Synthesis of 1,3-Mercaptoalkanols4 Photo-Biocatalysed Cascade Reactions5 Conclusions

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection.

The unprecedented Trametes versicolor laccase/TEMPO-catalyzed aromatization of 2,5-dihydrofurans to furans is described. A variety of furan derivatives have been synthesized in moderate to high con...

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral 1,2-mercaptoamines were then deracemized through enzymatic resolution of the racemates using monoamine oxidase (MAO-N) biocatalysts.

The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial biofilms is reported. Four carbonyl compounds of general formula fac-[Mn(N∧N)(CO)3(L)] have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435–450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay). The antibacterial activity of the four PhotoCORMs has been investigated against a panel of ESKAPE bacteria. The compounds 1–3 were found to be effective antibacterials at low concentrations against multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii when photoactivated with blue-light. In addition, the PhotoCORMs 1–2 were found to inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii bacterial biofilms at low concentrations (MIC = 4–8 μg/mL), turning out to be promising candidates to combat antimicrobial resistance. The antibacterial and biofilm inhibitory effect of the PhotoCORMs is plausibly due to the release of CO as well as the formation of phenanthroline photo-by-products as revealed by spectroscopy and microbiology experiments.

The enantioselective synthesis of α‐thiocarboxylic acids by biocatalytic dynamic kinetic resolution (DKR) of nitrile precursors exploiting nitrilase enzymes is described. A panel of 35 nitrilase biocatalysts were screened and enzymes Nit27 and Nit34 were found to catalyse the DKR of racemic α‐thionitriles under mild conditions, affording the corresponding carboxylic acids with high conversions and good‐to‐excellent ee. The ammonia produced in situ during the biocatalytic transformation favours the racemization of the nitrile enantiomers and, in turn, the DKR without the need of any external additive base., Nitrilase biocatalysts catalyse the dynamic kinetic resolution (DKR) of α‐thionitriles affording enantiomerically pure α‐thiocarboxylic acids under mild conditions. The DKR is favoured by the ammonia formed in situ during the biotransformation.

The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure‐based virtual screening approach using the ZIKV NS5‐MTase. A novel series of molecules with a carbazoyl‐aryl‐urea structure has been discovered and a library of analogues has been synthesized. The new compounds inhibit ZIKV MTase with IC50 between 23–48 μM. In addition, carbazoyl‐aryl‐ureas also proved to inhibit ZIKV replication activity at micromolar concentration., Novel antivirals targeting ZIKA virus: The recent outbreaks of Zika virus (ZIKV) worldwide make the discovery of novel antivirals a priority. Using a structure‐based virtual screening approach we were able to identify and develop a novel series of carbazoyl‐urea derivatives that are able to inhibit the ZIKV NS5‐MTase as well as ZIKV replication at micromolar concentration.

The biocatalytic aromatization of indolines into indole derivatives exploiting monoamine oxidase (MAO-N) enzymes is presented. Indoline substrates were prepared via photocatalytic cyclization of arylaniline precursors or via arylative dearomatization of unsubstituted indoles and in turn chemoselectively aromatized by the MAO-N D11 whole cell biocatalyst. Computational docking studies of the indoline substrates in the MAO-N D11 catalytic site allowed for the rationalization of the biocatalytic mechanism and experimental results of the biotransformation. This methodology represents an efficient example of biocatalytic synthesis of indole derivatives and offers a facile approach to access these aromatic heterocycles under mild reaction conditions.

Made available in DSpace on 2020-12-12T02:32:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-05-14 A series of N-phenyl-2,5-dimethylpyrrole derivatives, designed as hybrids of the antitubercular agents BM212 and SQ109, have been synthesized and evaluated against susceptible and drug-resistant mycobacteria strains. Compound 5d, bearing a cyclohexylmethylene side chain, showed high potency against M. tuberculosis including MDR-TB strains at submicromolar concentrations. The new compound shows bacteriostatic activity and low toxicity and proved to be effective against intracellular mycobacteria too, showing an activity profile similar to isoniazid. School of Cancer and Pharmaceutical Sciences King's College London, 150 Stamford Street Dipartimento di Biotecnologie Chimica e Farmacia, via A. Moro 2 Tuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1 Centre for Clinical Microbiology University College London Mycobacteria Research Laboratory Department of Biological Sciences Institute of Structural and Molecular Biology Birkbeck University of London, Malet Street Department of Chemistry Faculty of Exact Sciences Bar-Ilan University Tuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1

The synthesis of enantiomerically pure 1,3-mercaptoalkanol volatile sulfur compounds through a one-pot photo-biocatalytic cascade reaction is described. Two new KRED biocatalysts with opposite enantioselectivity were discovered and proved to be efficient on a wide range of substrates. The one-pot cascade reaction combining photocatalytic thio-Michael addition with biocatalytic ketoreduction in an aqueous medium provides a green and sustainable approach to enantiomerically pure 1,3-mercaptoalkanols in high yields with excellent enantioselectivity.

Propargylamines are a versatile class of compounds which find broad application in many fields of chemistry. This review aims to describe the different strategies developed so far for the synthesis of propargylamines and their derivatives as well as to highlight their reactivity and use as building blocks in the synthesis of chemically relevant organic compounds. In the first part of the review, the different synthetic approaches to synthesize propargylamines, such as A3 couplings and C-H functionalization of alkynes, have been described and organized on the basis of the catalysts employed in the syntheses. Both racemic and enantioselective approaches have been reported. In the second part, an overview of the transformations of propargylamines into heterocyclic compounds such as pyrroles, pyridines, thiazoles, and oxazoles, as well as other relevant organic derivatives, is presented.

A chemoenzymatic cascade process for the sustainable production of pyrroles has been developed. Pyrroles were synthesized by exploiting the previously unexplored aromatizing activity of monoamine oxidase enzymes (MAO-N and 6-HDNO). MAO-N/6-HDNO whole cell biocatalysts are able to convert 3-pyrrolines into pyrroles under mild conditions and in high yields. Moreover, MAO-N can work in combination with the ruthenium Grubbs catalyst, leading to the synthesis of pyrroles from diallylamines/-anilines in a one-pot cascade metathesis–aromatization sequence.

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.

Compounds incorporating guanidine moieties constitute a versatile class of biologically interesting molecules with a wide array of applications. As such, guanidines have been exploited as privileged structural motifs in designing novel drugs for the treatment of various infectious and non-infectious diseases. In designing anti-infective agents, this moiety carries great appeal by virtue of attributes such as hydrogen-bonding capability and protonatability at physiological pH in the context of interaction with biological targets. This review provides an overview of recent advances in hit-to-lead development studies of antimicrobial guanidine-containing compounds with the aim to highlight their structural diversity and the pharmacological relevance of the moiety to drug activity, insofar as possible. In so doing, emphasis is put on chemical and microbiological properties of such compounds in relation to antibacterial, antifungal and antimalarial activities.

Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes.

A sustainable MAO-N biocatalyzed process for the synthesis of pyridines from aliphatic tetrahydropyridines (THP) has been developed. Pyridine compounds were synthesized under mild reaction conditions and with high conversion, exploiting MAO-N whole cells as aromatizing biocatalysts. The kinetic profile of the whole cell biocatalytic transformation was finally investigated via in situ 19F NMR.

S-alkenyl-N-arylthiocarbamates are formed from allylic alcohols by sigmatropic rearrangement and isomerization or C═C bond cleavage. They undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may undergo N to C aryl migration to yield thiocarbamates with tertiary substituents. A simple base-promoted alcoholysis reveals a series of hindered tertiary thiols with branched carbon skeletons.

A simple and versatile microwave-assisted protocol for the synthesis of 2-aminothiazoles has been developed. The domino reaction of propargylamines and isothiocyanates in the presence of catalytic PTSA leads to the selective synthesis of 2-aminothiazoles at temperatures above 130 °C and in a few minutes. The same reaction carried out at lower temperatures leads to the formation of the tautomeric 2-amino-4-methylenethiazolines.

A fast, versatile and practical microwave-assisted multicomponent protocol for the synthesis of substituted benzofuran-2-carboxamides has been developed. The present method proved to be effective on a series of commercially available amines, 2′-hydroxyacetophenones, aldehydes, and benzonitriles and could be exploited in drug-discovery campaigns for the rapid identification of biologically active hit compounds.

A fast, versatile and practical microwave-assisted multicomponent protocol for the synthesis of substituted benzofuran-2-carboxamides has been developed. The present method proved to be effective on a series of commercially available amines, 2’-hydroxyacetophenones, aldehydes and benzonitriles and could be exploited in drug-discovery campaigns for the rapid identification of biologically active hit compounds.

Naturally occurring polyamines (PAs) play a pivotal role in the life of all organisms from bacteria to man. The human PAs putrescine, spermidine, and spermine are fundamental for cell viability, having a multitude of in vivo functions, and their study is an expanding field of research. The polycationic nature of these polyamines is important for their biological activities and for their in vivo interaction with macromolecules such as enzymes or the polyanionic nucleic acids. Several reviews have been reported so far on the chemistry, synthesis, and biological properties of polyamines. However, a particular class of polyamines, namely, the guanylated polyamines, attracted the attention of many chemists and biologists in the last decades. A guanylated polyamine is a polyamine with one or more of its amino moieties as part of a guanidine function. These compounds can be sometimes referred to as polyaminoalkylguanidines. Replacement of an amino group in a biologically active polyamine compound by the strongly basic guanidinium results often in a significant increase of its potency and/or selectivity. In fact, the guanidine group is a common structural key element in a variety of natural and synthetic compounds, which show interesting biological properties or chemical behavior and have therefore found important applications in medicinal, bioorganic, supramolecular chemistry, and, most recently, asymmetric synthesis. A guanidinium group is commonly used by proteins and enzymes to recognize and bind anions through ion pairing and hydrogen bonding. The specific patterns of hydrogen bonding recognition together with the high basicity (pKa ≈ 13.5) makes the guanidium group able to play several key roles in recognition, electrophilic catalysis, and biological activity in many enzymes. As a consequence, guanylated polyamines may possess biochemical and biophysical properties amplified with respect to their parent polyamines. Moreover, being strictly related to natural bioamines and amino acids, the guanylated polyamines often have high solubility in water and bioavailability, which makes them excellent drugs or lead compounds. Guanylated polyamines (in particular guanylated diamines and triamines) play important roles in biological processes and might be produced directly by plants, animals, and humans. However, despite their simple chemical structures, these compounds showed difficulties from a synthetic point of view, mostly due to the nature of guanidine moiety, which makes these compounds highly polar and hard to handle and to purify. In addition, the presence of two or more nitrogens or guanidine moieties represents an additional issue: for instance, the regioselctive guanylation of polyamines still represents a big challenge for chemists. Different synthetic methodologies have been reported to overcome these issues such as the shrewd use of a protecting group strategy or the use of solid-phase synthesis. Moreover, possessing these compounds different reactive moieties, side reactions sometimes constitute a problem. This review will cover systematically the preparation methodologies and chemical properties of guanylated diamines, triamines, and, more generally, polyamines. Finally, a description of their most important biological properties will be reported.

Three simplified "non-natural" natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10(-6) M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp.

A rapid protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel/hetero Diels–Alder reaction (DKHDA) has been developed for the synthesis of 2,3-dihydropyran[2,3- c ]pyrazoles. The reported procedure could be used for the fast generation of novel substituted 2,3-dihydropyran[2,3- c ]pyrazoles with potential anti-tuberculosis activity.

A new synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones was developed as a domino alkylation-cyclization reaction of propargyl bromides with thioureas and thio¬pyrimidinones, respectively. Domino reactions were performed under microwave irradiation leading to desired compounds in a few minutes and high yields

The synthesis of new and innovative macrocyclic amidinoureas from linear di-Boc-guanidino-alkylamines related to guazatine was accomplished. The macrocyclization reaction proceeds under mild conditions affording 11- to 16-membered rings with a new and previously undescribed structure in good yields. Enantiomerically pure macrocyclic amidinoureas were also synthesised. The strict correlation between macrocyclic amidinoureas and the natural productguazatine makes them very actractive also from a biological point of view.

A small library of 2-deacetoxytaxinine J (DAT-J) 1 derivatives was synthesised and tested in vitro for their reversal activity in human mammary carcinoma MDR cell line MCF7-R. One of the new taxoids showed to be active at 0.1 microM when tested in combination with paclitaxel.

The C13-C18 fragment 3 of the novel antibiotic branimycin was prepared along two highly stereocontrolled routes. The first one uses a standard Roush crotylation protocol, whereas the second one proceeds via an allenyl silane propargylation with unexpected stereochemical consequences, which are discussed in detail.

Enyne cross metathesis of propargylamines with ethyl vinyl ether enables the one-pot synthesis of substituted pyrroles. A series of substituted pyrroles, bearing alkyl, aryl, and heteroaryl substituents, has been synthesized in good yields under microwave irradiation. The reactions are rapid and procedurally simple and also represent a facile entry to the synthetically challenging 1,2,3-substituted pyrroles. The value of the methodology is further corroborated by the conversion of pyrroles into 3-methyl-pyrrolines and the derivatization of the 3-methyl-substituent arising from the metathesis reaction.

The discovery of a novel class of HCV inhibitors is described. The new amidinourea compounds were designed as isosteric analogues of the antiviral drug moroxydine. The two derivatives 11g and 11h showed excellent HCV inhibition activity and viability and proved to inhibit a step(s) of the RNA replication. The new compounds have been synthesized in only three synthetic steps from cheap building blocks and in high yields, thus turning to be promising drug candidates in the development of cheaper HCV treatments.

The addition of n-butyllithium to alkenylthiocarbamates in the presence of (−)-sparteine or the (+)-sparteine surrogate leads to asymmetric carbolithiation, and returns enantiomerically enriched thiocarbamate derivatives of secondary thiols. In THF, with the (+)-sparteine surrogate, in situ aryl migration leads to an enantiomerically enriched tertiary thiol derivative. Remarkably, the two pseudoenantiomeric chiral ligands do not always give enantiomeric products, probably as a result of a complex interplay of kinetic and thermodynamic control. In situ IR and NMR studies of a stable, hindered lithiated thiocarbamate demonstrated its chemical and configurational stability over a period of hours at 0 °C.

Enyne cross metathesis of propargylamines with ethyl vinyl ether enables the one-pot synthesis of substituted pyrroles. A series of substituted pyrroles, bearing alkyl, aryl, and heteroaryl substituents, has been synthesized in good yields under microwave irradiation. The reactions are rapid and procedurally simple and also represent a facile entry to the synthetically challenging 1,2,3-substituted pyrroles. The value of the methodology is further corroborated by the conversion of pyrroles into 3-methyl-pyrrolines and the derivatization of the 3-methyl-substituent arising from the metathesis reaction.

A variety of highly functionalized cis-decalin systems have been prepared by means of the stereoselective transannular Diels-Alder (TADA) reaction of a (Z,E,Z,Z)-tetraene macrolide, and by means of intramolecular nitrile oxide olefin (INOC) or ring-closing metathesis (RCM) annulations to quinic acid derivatives.

Chiral 1-arylpropargyl amides, which are resistant to undergoing ethylene–alkyne cross-metathesis at atmospheric pressure, were reacted under microwave irradiation to afford enantiomerically enriched 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes within a few minutes. Enantiomerically enriched amides underwent ethylene–alkyne cross-metathesis with retention of configuration at the propargylic/allylic position. A series of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes were synthesised with ee ⩾95%; these latter compounds could be used as building blocks for the synthesis of new antifungal and antiaromatase agents.

A variety of substituted 1-aryl-2-propenylamines of high enantiomeric purity were prepared via lipase-catalysed resolution of the corresponding racemates. (R)-1-Phenyl-2-propenylamine was further synthesised into (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropanoic acid methyl ester, the side chain of Taxol®.

The treatment of 1-cyanoethyl ureas (I) with sBuLi leads to iminohydantoins (II) as a result of an aryl migration and a cyclization.

The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA-PB1 inhibitors.

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

S-Alkenyl-N-arylthiocarbamates undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may undergo N to C aryl migration to yield thiocarbamates with tertiary substituents.

Novel macrocyclic amidinourea derivatives 11, 18, and 25 were synthesized and evaluated as antifungal agents against wild-type and fluconazole resistant Candida species. Macrocyclic compounds 11 and 18 were synthesized through a convergent approach using as a key step a ring-closing metathesis macrocyclization reaction, whereas compounds 25 were obtained by our previously reported synthetic pathway. All the macrocyclic amidinoureas showed antifungal activity toward different Candida species higher or comparable to fluconazole and resulted highly active against fluconazole resistant Candida strains showing in many cases minimum inhibitory concentration values lower than voriconazole.

Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration.

The acylation of 4-(2-aminoethylthio)-7-nitrobenzofurazan has been investigated. Depending on the use of the base, a competitive Smiles rearrangement occurs during the acylation step leading to the formation of N-acyl and/or fluorescent S-acyl derivatives. The acylating agent also affects the ratio of N/S acylated isomers.

Naturally occurring polyamines (PAs) play a pivotal role in the life of all organisms from bacteria to man. The human PAs putrescine, spermidine, and spermine are fundamental for cell viability, having a multitude of in vivo functions, and their study is an expanding field of research. The polycationic nature of these polyamines is important for their biological activities and for their in vivo interaction with macromolecules such as enzymes or the polyanionic nucleic acids. Several reviews have been reported so far on the chemistry, synthesis, and biological properties of polyamines. However, a particular class of polyamines, namely, the guanylated polyamines, attracted the attention of many chemists and biologists in the last decades. A guanylated polyamine is a polyamine with one or more of its amino moieties as part of a guanidine function. These compounds can be sometimes referred to as polyaminoalkylguanidines. Replacement of an amino group in a biologically active polyamine compound by the strongly basic guanidinium results often in a significant increase of its potency and/or selectivity. In fact, the guanidine group is a common structural key element in a variety of natural and synthetic compounds, which show interesting biological properties or chemical behavior and have therefore found important applications in medicinal, bioorganic, supramolecular chemistry, and, most recently, asymmetric synthesis. A guanidinium group is commonly used by proteins and enzymes to recognize and bind anions through ion pairing and hydrogen bonding. The specific patterns of hydrogen bonding recognition together with the high basicity (pKa ≈ 13.5) makes the guanidium group able to play several key roles in recognition, electrophilic catalysis, and biological activity in many enzymes. As a consequence, guanylated polyamines may possess biochemical and biophysical properties amplified with respect to their parent polyamines. Moreover, being strictly related to natural bioamines and amino acids, the guanylated polyamines often have high solubility in water and bioavailability, which makes them excellent drugs or lead compounds. Guanylated polyamines (in particular guanylated diamines and triamines) play important roles in biological processes and might be produced directly by plants, animals, and humans. However, despite their simple chemical structures, these compounds showed difficulties from a synthetic point of view, mostly due to the nature of guanidine moiety, which makes these compounds highly polar and hard to handle and to purify. In addition, the presence of two or more nitrogens or guanidine moieties represents an additional issue: for instance, the regioselctive guanylation of polyamines still represents a big challenge for chemists. Different synthetic methodologies have been reported to overcome these issues such as the shrewd use of a protecting group strategy or the use of solid-phase synthesis. Moreover, possessing these compounds different reactive moieties, side reactions sometimes constitute a problem. This review will cover systematically the preparation methodologies and chemical properties of guanylated diamines, triamines, and, more generally, polyamines. Finally, a description of their most important biological properties will be reported.

The use of in situ generated organocopper instead of simple Grignard reagents is the key factor to suppress undesirable side homocoupling and to lead the reaction to completion.