A-mini-review-on-Biginelli-adducts-with-notable-pharmacological-properties

MINI REVIEW

A mini-review on Biginelli adducts with notable pharmacological

properties

A

ngelo de Fa tima a ,*,Taniris C.Braga a ,Leonardo da https://www.wendangku.net/doc/4f15710156.html,o a ,Bruna S.Terra a ,Breno G.F.Oliveira a ,Daniel L.da Silva a ,Luzia V.Modolo b

a

Departamento de Qu?′m ica,Instituto de Cie ?ncias Exatas,Universidade Federal de Minas Gerais,Av.Pres.Anto ?nio Carlos,

A R T I C L E I N F O Article history:

Received 18August 2014

Received in revised form 5October 2014

A B S T R A C T

Since the disclosure of Biginelli reaction by the chemist Pietro Biginelli,functionalized 3,4-dihy-dropyrimidin-2(1H )-ones/thiones (DHPMs)have emerged as prototypes for the design of compounds with a broad variety of biological activities.This mini-review describes over 100Biginelli adducts demonstrated to be promising anticancer,inhibitors of calcium channel,

*Corresponding author.Tel.:+553134096373;fax:+553134095700.

E-mail address:adefatima@qui.ufmg.br (A

.de Fa tima).

https://www.wendangku.net/doc/4f15710156.html,/10.1016/j.jare.2014.10.006

2090-1232a2014Production and hosting by Elsevier B.V.on behalf of Cairo University.

Accepted 24October 2014

Available online 1November 2014Keywords:

Biginelli adducts

Antiproliferative activity cancer Calcium channel

Antimicrobial activity

anti-in?ammatory,antimicrobial and antioxidant agents.Thus,this compilation presents the

most notable in vitro and in vivo results for such fascinating class of organic compounds.

a2014Production and hosting by Elsevier B.V.on behalf of Cairo University.

Introduction

The year 1891was a milestone for the discovery of a new class of heterocycle molecules named

Biginelli adducts after the chemist Pietro Biginelli who ?rst report the simple one-pot process that furnish organic compounds of this kind [1].The multicomponent reaction that provides Biginelli adducts,also

Dr.de Fa

tima is the coordinator of the Network for the Development of Novel Urease Inhibitors (https://www.wendangku.net/doc/4f15710156.html, )and Group of Studies on Organic and Biological Chemistry.His research inter-ests include the synthesis of molecules with biological,functional pro?le and the evaluation of their activities against cancer cells,fungi,bacteria and virus of clinical interest.

Taniris Ca?ero Braga was born in 1990.She earned her BSc.degree in Chemistry in 2013at the Federal University of Minas Gerais (MG,Brazil)when she joined the Graduation Program in Chemistry to start her Master studies under the mentoring of

Dr.de Fa

tima.Her research interests are in the ?eld of Organic and Medicinal Chemistry.

Leonardo da Silva Neto is Pharmacist and received his MSc.degree in Chemistry in 2011from the Federal University of Minas Gerais (MG,Brazil).He is currently a PhD student at the same University developing research under the mentoring of Dr.de Fa

tima.MSc.Silva Neto research interests are focused on the synthesis of calix[n ]arenes and H 2S-releasing com-pounds and their biological pro?les.

Bruna Silva Terra was born in 1988.She earned her BSc.degree in Pharmacy in 2011at the State University of Londrina (PR,Brazil).She received her MSc.degree in Chemistry in 2013from the Federal University of Minas Gerais (MG,Brazil).She is currently performing her PhD studies in Chemistry under the mentoring

of Dr.de Fa

tima.Her research interests are in the ?eld of Organic and Medicinal Chemistry.

to perform his Master studies in Organic Chemistry.His research interests are in the ?elds of Organic Synthesis and Biological Chemistry.

Daniel Leite da Silva received his BSc.and MSc.in Chemistry in 2009and 2011from the Federal University of Vic osa (MG,Brazil)and Federal University of Minas Gerais (MG,Brazil),respectively.He is currently performing his PhD studies in Chemistry under the mentoring of Dr.de Fa

tima.His research interests are focused on the synthesis and biological activity of Biginelli adducts.

Luzia Valentina Modolo received her PhD degree in Functional and Molecular Biology in 2004from the State University of Campinas (SP,Brazil).She is currently the Head of the Department of Botany at the Federal University of Minas Gerais (MG,Brazil).Dr.Modolo is also the coordinator of the Network for the Development of Novel Urease Inhibitors (https://www.wendangku.net/doc/4f15710156.html, )and Group of Studies on Plant Biochemistry (https://www.wendangku.net/doc/4f15710156.html, ).

Her research interests include the signalling processes coordinated in plant tissues in response to environmental stress,plant nutrition and plant secondary metabolism.

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known as 3,4-dihydropyrimidin-2(1H )-ones/thiones (DHPMs;Fig.1),involves the reaction of 1,3-dicarbonyl compounds with aldehydes and (thio)urea [2].Three main mechanisms have been proposed for the Biginelli reaction,but this subject is still under debate in the literature.Detailed information on these three mechanisms is addressed elsewhere [3].Variation of all three building blocks has broadened the molecular diversity of DHPMs with wide variety biological activities.Indeed,a series of pharmacological properties of DHPMs have been reported,which include antiviral,antitumor,anti-in?am-matory,antibacterial,antifungal,anti-epileptic,antimalarial,antileishmanial,among others.The next topics will cover for some of the most notable Biginelli adducts reported as antican-cer,calcium channel inhibitors,anti-in?ammatory,antimicro-bial and antioxidant agents since the listed pharmacological properties are some of the most investigated for DHPMs.

Anticancer activity

Biginelli adducts are promising compounds for the treatment of cancers in which monastrol (1)is the most studied with this regard (Fig.2).The ?rst work that explored the effect of monastrol on cancer cells was reported in 1999[4].Monastrol was found to interrupt mitosis by inhibiting the motor activity of the kinesin Eg5,a protein involved in spindle bipolarity formation [5].

Since then,monastrol has been used as an inspiration for the design of new anticancer agents.Out of eleven monastrol analogues synthesized,the Biginelli adduct 2was identi?ed as a potent anticancer agent based on the concentration of this adduct necessary to inhibit cell growth by 50%(EC 50,IC 50or GI 50)as it follows:MCF-7breast (1.9l g mL à1),786-0kidney (2.0l g mL à1),HT-29colon (2.5l g mL à1),UACC.62mela-noma (6.0l g mL à1)and OVCAR03ovarian (6.6l g mL à1)cancer cells [5].

Compounds 3–10(Fig.2)were described as some of the most effective pyrimidinone-peptoid hybrids against SK-BR-3breast cancer cells,exhibiting GI 50values in the range of 6.0–8.8l M [6].

Biginelli adducts bearing cinnamoyl (11and 12),pyridin-4-yl (13)or furan-2-yl (14and 15)groups (Fig.2)showed signif-icant cytotoxic effects against the MCF-7breast cancer cell line,in which at concentration of 50l g mL à1prevented cell growth by at least 70%[7].

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Biginelli adducts-amide derivatives such as16and17 (Fig.3)exhibited moderate antiproliferative activity against HepG2epithelial carcinoma in which the IC50value for both compounds was ca.120l g mLà1[8].On the other hand, the derivatives17and18showed IC50values of around 190l g mLà1against HeLa hepatocellular carcinoma cells [8].

Other monastrol(1)analogues were synthesized and tested against cancer cell lines of different histological origins[9]. Twelve Biginelli adducts(19–30;Fig.3)were more potent than monastrol(GI50in the range of4.0–29.6l g mLà1)against one or more of the seven cancer cell lines studied(Table1)[9]. Notably,compound19was determined to be over90-and 10-fold more potent than monastrol(1)against U251glioma cells and NCI-ADR/RES multiple drug-resistant ovarian cancer cells,respectively(Table1).Compound20was found to be almost90-fold more potent than monastrol against NCI-ADR/RES multiple drug-resistant ovarian cancer cells while the GI50value for21is about30-fold lower than that of monastrol toward U251cells(Table1).The results also indicate that six Biginelli adducts present GI50values at least 5-fold lower than those of monastrol against some of the following cancer cells:U251glioma,NCI-ADR/RES multiple drug-resistant ovarian,786renal,NCI-H460non-small lung, PC-3prostate,OVCAR-03ovarian and HT-29colon cancer (Table1).

Morphological alterations in MCF-7breast cancer cells that culminated in the death of over80%cells were observed after72h of treatment with the Biginelli adducts31(dimethy-lenastron)to33(Fig.3)at concentrations in the range of 400l M to1mM.Such compounds showed minute toxic effects against?broblast healthy cells[10].

Table1Potency(in folds)of Biginelli adducts relative to monastrol(1)with respect to the antiproliferative activity against cancer cells of different histological origins.Adapted from da Silva and coworkers[9].

Biginelli adduct U251NCI-ADR/RES786-0NCI-H460PC-3OVCAR-03HT-29 1996.010.6(–)(–)(–)9.0(–)

20 5.088.8(–)(–)(–)8.4 1.0 2131.0 1.0(–)(–)(–)7.5 1.0

22 1.07.0(–)(–) 1.014.3 1.0

23 1.0 1.0 1.0 3.011.0 6.5 1.0

24 5.77.0(–)(–)(–)(–) 1.0

25 1.0 1.0(–)(–)(–)11.0 1.0

26 4.7 2.0(–)(–)(–) 2.4 1.0

27(–) 4.0(–)(–)(–)(–) 1.0

28 3.08.0 1.5 3.0(–) 1.4 3.0

29 4.0(–)(–)(–)(–) 1.7 1.7

30 1.0 6.0(–)(–) 3.0(–) 1.0

GI50values for monastrol were in range of4.0–29.6l g mLà1[9].(–)Indicates that the Biginelli adduct was less potent than monastrol(1).U251, glioma cells;NCI-ADR/RES,multiple drug-resistant ovarian cancer cells;786,renal cancer cells;NCI-H460,non-small lung cancer cells;PC-3, prostate cancer cells;OVCAR-03,ovarian cancer cells and HT-29,colon cancer cells.

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Calcium channel inhibition

Dihydropyridines such as nifedipine were introduced to the market in1975for the treatment of cardiovascular diseases (hypertension,cardiac arrhythmias and angina)due to the ability to inhibit calcium channels[11].After the discovery of this drug several analogues,including Biginelli adducts,were synthesized to verify the potential to block calcium channels.

A structure–activity relationship study with Biginelli adducts was reported in1990with respect to the ability to target calcium channels[12,13].It was determined that thio-adducts were the most potent Biginelli compounds in compar-ison with oxo-and aza-analogues[12,13].In vitro assays revealed that the adduct bearing a nitro group at ortho-position of aromatic ring was more effective antihypertensive compound than that containing CF3or Cl as substituent (Fig.4)[13].Interestingly,the presence of an isopropyl ester group at C5improved the Biginelli adduct potency by10-and60-fold in comparison with the effect of the ones bearing an ethyl ester or methyl ester group at the same carbon, respectively[13].Although compounds bearing substituents at N3are potent calcium channel blockers in vitro,their anti-hypertensive properties are lost in in vivo experiments as a result of metabolization by rats[13].Additionally,oxo-ana-logues were found to be more stable as homogenates from rat liver did not present metabolites derived from such these compounds[13].Finally,the stereocenter at C4also plays a key role in the activity of such Biginelli adducts toward cal-cium channel;the(R)-enantiomer(34a;Fig.4)is750-fold more potent vasorelaxant agent than the corresponding(S)-enantiomer(34b;Fig.4)[13].Atwal and coworkers then substituted the acyl at N3for a carbamoyl group to check whether such structural changes would affect the inhibition of calcium channel by Biginelli adducts related to34[14]. The best compounds(35–39;Fig.4)tested in vitro exhibited IC50values of3,12,13,16and60nM,respectively.Thus,it was concluded that the presence of substituents at carbamoyl group in?uenced compounds potency as it follows:benzyl group>hydrogen,methyl or ethyl group>isopropyl group [14].Compounds bearing1-(phenylmethyl)-4-piperidinyl car-bamate at N3were described as the most promising calcium channel blockers in in vivo experiments,in which the presence of CF3at ortho-position of aromatic ring enhanced com-pounds effect when compared to the ones bearing nitro group [15].Additionally,?uorine at para-position of benzyl moiety prevented the Biginelli adduct from metabolization by rat cells and conferred much higher potency than that of the reference drug amlodipine.Again,in vitro experiments demonstrated that the(R)-enantiomer(40a;Fig.4)is much more potent than the corresponding(S)-enantiomer(40b;Fig.4),since the

Biginelli adducts and biological activities367

former exhibits an IC 50value of 15nM while the IC 50value for the latter is determined to be higher than 1000nM [15].

The thio -Biginelli adducts 41and 42were determined to be relaxant agents as effective as the reference drug nicardipine (inhibition of stimulus by 35.5±4.2%)on KCl-stimulated lamb carotid strips when used at 100l M [16].Compounds 41and 42present a Cl atom as substituent at meta -and para -position,respectively (Fig.4).The relaxant effect of the thio -Biginelli adduct 43(Fig.4)on KCl-stimulated contractions in rat thoracic aorta was comparable to that of nicardipine (inhibition of stimulus by 20.5±2.9%)[17].Other oxo -Biginelli adducts were investigated for the calcium channel blockage-dependent relaxant effect on KCl-stimulated lamb carotid https://www.wendangku.net/doc/4f15710156.html,pounds containing Br,CH 3or CF 3at ortho -position or Br at meta -position in aromatic ring (44–47;Fig.4)at 1l M were either as potent or as more potent than nicardipine that at the same concentration was able to inhibit the stimulus by 2.5±1.8%[18].

The acetylated thio -Biginelli adduct derivative 48(Fig.4)effectively caused the relaxation of KCl-stimulated guinea pig ileum as attested by its value of negative log molar concen-tration of antagonist required to reduce the response of agonist by 50%(PA 2=6.06)in relation to the reference drug verapamil [19].

Anti-in?ammatory activity

In?ammation process can be characterized by ?ve phases that may or may not occur simultaneously,named pain,heat,red-ness,swelling and ultimately loss of function.They comprise a defensive body response to invasion of a foreign material.Acute in?ammation can cause several damages in tissues or

organs.The anti-in?ammatory potential of a certain molecule

can be investigated by various means,such as the analgesic effect using paw edema as model,the inhibition of proin?am-matory cytokines (e.g.tumor necrosis factor (TNF-a )and interleukin 6(IL-6))[20],the effect on prostaglandin E 2and/or hialuronidase,nitric oxide synthase (iNOS)and cyclooxygenase-2(COX-2)and transient receptor A1(TRPA1),among others [20–24].

Biginelli adducts have received great attention with respect to their potential as anti-in?ammatory agents.Based on the duration of action and percentage of in?ammation inhibition on Albino rats paw edema,the propanoic acid derivatives thio -adducts (49–53;Fig.5)were found to be the most promising anti-in?ammatory compounds when compared to diclofenac,a reference drug [25].The Biginelli derivative 54,which bears a 1,3,4-oxadiazol-2-yl moiety (Fig.5),controls in?ammation process by inhibiting the carrageenan-induced rat paw edema by 75%after 3h of treatment,an effect comparable to that exhibited by diclofenac [26].

The potential of the thio -analogue Biginelli adduct 55(Fig.5)to inhibit the production of proin?ammatory cytokines in LPS-induced human monocytic leukemia cells (THP-1)was addressed [20].The production of TNF-a and IL-6in THP-1cells in the presence of compound 55at 10l M was 78%and 96%lower than that of cells incubated in the absence of this Biginelli adduct,respectively.Under the same experimental conditions,dexamethasone (reference drug at 1l M)inhibit TNF-a and IL-6production by 71%and 84%,respectively [20].

Chronic in?ammation is known to be associated with increased activity of hyaluronidases,enzymes that catalyzes the degradation of hyaluronic acid [27,28].Based on

this,

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Gireesh and coworkers performed molecular docking studies using some Biginelli adducts and related derivatives to identify compounds with potential to inhibit hyaluronidase[24]. Indeed,in vitro assays con?rmed that100l g of compounds 56–59(Fig.5)was able to inhibit the activity of hyaluronidase (3–5units)in the range from89%to100%.Similar results were achieved when compounds56–59were substituted for indomethacin,a reference drug[24].

The anti-in?ammatory properties of Biginelli adducts60–62(Fig.5)were attested by their capacity to inhibit NO production in LPS-activated microglia at IC50values ranging from41.3to67.3l M[29].Compound60was also the most potent among these Biginelli adducts in the inhibition of pros-taglandin E2(PGE2)production and iNOS and COX-2genes expression.Additionally,60negatively affected the production of TNF a and interleukin-1b(IL-1b)[23].

Biginelli adducts bearing meta-substituents have been described as very promising anti-in?ammatory agents in stud-ies carried out with human embryonic kidney293cell lines (HEK293)overexpressing the transient receptor potential A1 (TRPA1)either from human or rat[22].Thus,compounds 63a-b and64a-b(Fig.5)were able to inhibit both human and rat TRPA1at concentrations ranging from4to75nM. The R isomers(63b and64b),however,were identi?ed as the most potent inhibitors acting on rat TRPA1at IC50values as low as4and12nM,respectively,while the IC50for the corresponding S isomers(63c and64c;Fig.5)were found to be higher than10,000nM[22].

Antibacterial activity

Biginelli compounds bearing a1,3-diarylpyrazole moiety(65–68;Fig.6)exhibited minimal inhibition concentration(MIC) of20ng mLà1,20ng mLà1,250ng mLà1and125ng mLà1 against the Mycobacterium tuberculosis H37Rv(MTB H37Rv),respectively[30,31].The effect of65and66on normal kidney-derived African green monkey cells(VERO line)was assessed,revealing that both Biginelli adducts are highly selec-tive to MTB H37Rv(selectivity index>500)[30].Other16 Biginelli adducts(69–74;Fig.6)were found to be as potent as or more potent than the reference drugs ethambutol (MIC=7.6l M)and cipro?oxacin(MIC=9.4l M)against MTB H37Rv.The MIC values for compounds69–74ranged from3.4to76.2l M[32].

Biginelli adducts and biological activities369

Compounds75and76,containing a nitro group and?uo-rine at para-position,respectively,exhibited MIC values of 12.5l g mLà1(for the former)and12.5–25.0l g mLà1(for the latter)against Escherichia coli,Klebsiella pneumonia, Pseudomonas aeruginosa,Salmonella typhi and Staphylococcus aureus,which make these compounds more potent than cipro?oxacin[33].Biginelli adducts bearing a 1,3-dihydro-2H-indol-2-one core showed moderate antibacte-rial activities(62.5–250.0l g mLà1)against Bacillus subtilis (MTCC-441), E.coli(MTCC-443),K.pneumonia(MTCC-109),P.aeruginosa(MTCC-1688),S.typhi(MTCC-98),S. aureus(MTCC-96)and Staphylococcus pyogenus(MTCC-442)[34].

Antiviral activity

Kim and coworkers showed the potential of some Biginelli adducts as agents for preventing human immunode?ciency virus HIV-1replication[35,36].Notably,compounds77–82 (Fig.6)compromised the HIV-1replication in CEMx174-LTR-GFP cells(clone CG8)by50%when employed at concentrations lower than90nM.At the same experimental conditions,the reference drug nevirapine exhibited an EC50 value of150nM[35,36].The(S)-enantiomer was determined to be more potent than the corresponding(R)-enantiomer with respect to the antiviral activity.Indeed,it was shown that(S)-77 is at least26-fold more potent than(R)-77[35,36].

The potential of the Biginelli-type pyrimidines83 (IC50=1.8l M)and84(IC50=0.9l M)against herpes sim-plex virus(HSV-KOS strain)was shown elsewhere(Fig.6) [37].Notably,the analogue84exhibited negligible toxicity toward the mammalian cells tested indicating its selectivity to the studied virus.A time-of-addition study was then performed with84revealing that the administration of such compound to cells2and4h post inoculation was suf?cient to negatively affect virus replication.The lack of inhibition of virus adhesion and/or entry to the cells suggests that compound84inhibits virus replication in late stages[37].Antifungal activity

Fungi have emerged worldwide as some of the most frequent causes of healthcare-associated infections.Invasive fungal infections can be life-threatening and the number of antifungal agents currently available in the market is very limited[38].

Although Biginelli adducts have been poorly explored with respect to the antifungal activity,some examples of promising compounds are described in the literature.Eleven Biginelli-type pyrimido[4,5-d]pyrimidine-2,5-diones were described as potential anti-Aspergillus niger and anti-Candida albicans agents,exhibiting MIC values raging from11to57l g mLà1 [39].The most active compounds(85–88;Fig.6)showed MIC values near to or lower than20l g mLà1in comparison with the reference antifungal clotrimazole,whose MIC values against A.niger and C.albicans were20and25l g mLà1, respectively.Thus,analogues bearing withdrawing groups, with exception of4-Cl substituent,were the most active against A.niger and C.albicans[39].

The Biginelli adducts75and76(Fig.6)ef?ciently inhibited the growth of C.albicans,Aspergillus?avus,Rhizopus sp.and Mucor sp.as attested by the MIC values in the range of12.5–25l g mLà1,being most of the time more potent than ampho-tericin B(MIC=25–50l g mLà1)[33].

According to Rajanarendar and coworkers[40],isaxole Biginelli adducts are promising antifungal agents against A. niger,Chrysosporium tropicum,Rhizopusoryzae,Fusarium mon-iliformae and Curvularia lunata.When tested at100l g mLà1, compounds89and90(Fig.6)were able to induce the forma-tion of a zone of fungal growth inhibition from60mm to 65mm against the strains tested,which confers to these compounds higher potency in comparison with clotrimazole (inhibition zone of up to35mm)[40].Studies of formation of zones of fungal growth inhibition were also carried out with C.albicans and Aspergillus parasiticus and the adducts91–93 (Fig.6)[41].An average zone of inhibition of16.5mm was veri?ed in cultures of C.albicans in the presence of Biginelli

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adducts at10l g mLà1,while clotrimazole triggered the formation of a21mm-inhibition zone.As for A.parasiticus, the inhibition zone in the presence of compounds91–93and clotrimazole(all at10l g mLà1)were,respectively,13mm, 17mm,18mm and22mm[41].

Antioxidant activity

Oxygen and nitrogen reactive species(ROS and RNS,respec-tively)are ubiquitous in nature being a result of electron escape from electron transport chain(present in mitochondria and chloroplast).The overproduction of ROS and/or RNS can be deleterious to cells if the cellular antioxidant system is not able to ef?ciently restore the normal levels,which can ultimately cause pathologies[9,42].

The?rst report on the antioxidant properties of Biginelli adducts was published in2006in a study that investigated the potential of such molecules to prevent ROS formation and lipid peroxidation in male adult albino Wistar rats[42]. The Biginelli adducts94and95(Fig.7)restored the lipid hydroperoxide to normal levels in liver cells when administered at200l M.These results indicate that the presence of a nitro group on aromatic ring is not mandatory for adduct95pre-venting lipid https://www.wendangku.net/doc/4f15710156.html,pounds94and96(Fig.7)were found to be more ef?cient than the corresponding nitro-ana-logues95and97(Fig.7)to prevent the overproduction of ROS[42].

The potency of the thio-adducts98and99(87.5%;Fig.7) to scavenge hydroxyl radicals was comparable to that of the reference antioxidant quercetol(92.3%)when all compounds were used at100l M[43].The thio-adducts22(Fig.3)and 100(Fig.7)exhibit IC50values of10l M and76l M, respectively,regarding the scavenging of2,2-diphenyl-1-pic-rylhydrazyl(DPPH)radicals[44].Also,compounds22and 100at300l M diminished,at similar extents,the lipid hydroperoxide levels in homogenates of cerebral cortex from rats[44].

The adduct101(Fig.7)effectively scavenged DPPH radicals exhibiting an IC50value of0.6mg mLà1,while the IC50value for gallic acid(a known radical scavenger)was

0.8l g mLà1[45].

A series of Biginelli adducts were tested by da Silva and coworkers to compare the ability of thio-and oxo-derivatives to scavenge RNS and ROS[9].Compounds19,21,25 (Fig.3)and102(Fig.7)were determined to be the most promising RNS scavengers among the tested adducts,as they showed IC50values of20.3,29.7,23.3and24.2l M, respectively,while resveratrol exhibited an IC50of34.4l M in reactions containing DPPH100l M.As for ROS scaveng-ing,the IC50values for19,21,25and102and resveratrol toward O2àwere33.0,25.7,122.3,78.0,121.4l M,respectively [9].

Compounds20(Fig.3)and103–105(Fig.7)were demonstrated to be as ef?cient as gallic acid in the scavenging of DPPH at40l g mLà1as the IC50values for these adducts ranged from2.1to5.0l g mLà1[46].

Concluding remarks

The diverse biological pro?le of Biginelli adducts brought perspectives for the development of novel drugs to improve human and animal health.Here,we compiled the effect of over 100Biginelli adducts on cancer cells,calcium channels,in?am-mation,microorganisms(bacteria,viruses and fungi)and ROS and RNS scavenging.Some progress has been made with respect to the mechanism of action by which monastrol(1) and related molecules trigger the inhibition of cancer cells growth.However,the mechanisms of action of Biginelli adducts that lead to the attenuation and/or prevention of other pathologies are still incipient.Therefore,advances in this matter will certainly contribute to the rational design of more ef?cient and selective calcium channel inhibitor,anti-in?am-matory,antimicrobial and antioxidant agents based on Biginelli adducts core.

Con?ict of interest

The authors have declared no con?ict of interest. Compliance with Ethics Requirements

This article does not contain any studies with human or animal subjects.

Acknowledgments

This work was?nancially supported,in part,by Conselho Nacional de Desenvolvimento Cient??co e Tecnolo gico (CNPq),Coordenac a o de Aperfeic oamento de Pessoal de N?vel Superior(CAPES)and Fundac a o de Amparo a Pesquisa do Estado de Minas Gerais(FAPEMIG).AdF and LVM are recipients of research fellowships from CNPq. References

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