Nitrocompostos contra Tripanossomatídeos - Heróis ou Vilões

19 Megazol ICk50 375 μM Tulahuén 424 μM LQ 291 μM Brener Change of position C5 to C4 23 4nitromegazol Nitroimidazolebased compounds designed against Trypan Nitro group was discussed icity when investigating st three different hap alkane analog has been activesite cysteine res e for designing covalent n indepth literature e tives synthesized so far cruzi T brucei and Nitrofurans and Nitro Since the bi pathogenic t zymes for example furylsemicarbazone d rhenium Re and rutl are used in the devel op complexes were eval pounds 47 displave Bioorg Med Chem Lett 75 2022 128930 Available online 24 August 2022 0960894X 2022 Elsevier Ltd All rights reserved Nitro compounds against trypanosomatidae parasites Heroes or villains Paulo Fernando da Silva SantosJúnior a Leandro Rocha Silva b Lucindo Jose QuintansJúnior a Edeildo Ferreira da SilvaJúnior b a Pharmaceutical Sciences Graduate Program PPGCS Federal University of Sergipe Sao Cristovao Sergipe 49100001 Brazil b Institute of Chemistry and Biotechnology Federal University of Alagoas AC Simoes Campus Lourival Melo Mota Avenue sn 57072970 Maceio Brazil A R T I C L E I N F O Keywords Nitrofuran Nitroindazole Nitroreductase Medicinal chemistry Trypanosoma Leishmania A B S T R A C T Chagas disease and Human African trypanosomiasis HAT are caused by Trypanosoma cruzi T brucei rhodesiense or T b gambiense parasites respectively while Leishmania is caused by parasites from the Leishmania genus In recent years many efforts have been addressed to develop inhibitors against these parasites especially nitro containing derivatives which can interfere with essential enzymes from the protozoa In this review all anti trypanosomatidae nitrocompounds reported so far are shown herein highlighting their activities and SAR an alyses providing all the benefits and problems associated with this ambiguous chemical group Finally this review paper will be useful for many research teams around the world which are searching for novel trypa nocidal and leishmanicidal agents Kinetoplastidae order comprises two families of flagellated eukaryotic parasites being uniflagellate trypanosomatids and biflagellate bodo nids in which the Trypanosomatidae family includes Leishmania and Trypanosoma genera These unicellular parasites cause human illnesses named Neglected Tropical Diseases NTDs by World Health Organiza tion WHO Among them Leishmania sp and Trypanosoma sp are the two main parasites responsible for causing lethal diseases in humans such as visceral leishmaniasis LV Chagas disease and human African trypanosomiases HAT13 Leishmaniasis is a complex containing20 protozoa from the Leishmania genus which is endemic in 97 countries affecting about 051 million new cases per year46 This disease can present different clinical manifestations such as Tegumentary Leish maniasis TL which causes lesions or nodules in the skin and mucosa of hosts corresponding to the most common form of this disease ac counting for 97 of global cases 90000 per year In contrast Visceral Leishmaniasis VL also known as KalaAzar affects the viscera of infected hosts78 However current pharmacotherapy remains restricted in which pentavalent antimonial drugs have been depreciated over liposomal amphotericin B as the firstline treatment910 In addi tion both treatments have several adverse effects being ineffective especially in the chronic phase1112 A prototype has been developed DNDi0690 a nitroimidazole derivative that has shown promising in vitro activity against both visceral leishmaniasis and cutaneous leish maniasis13 Trypanosoma brucei rhodesiense and T b gambiense are two parasitic protozoa responsible for acute and chronic forms of HAT respectively Also it is known as sleeping sickness which is an endemic NTD transmitted by tsetse flies in subSaharan Africa representing a serious health risk to 60 million people The WHO estimates that30000 new cases have being reported per year1415 Treatment of HAT is solely dependent upon an offset of a few drugs such as fex inidazole suramin pentamidine melarsoprol and eflornithine which frequently are associated with low therapeutic indexes Moreover these drugs lead to high toxicities and unacceptable side effects along with administration difficulty and the emergence of resistant parasites All these problems reinforce the urgent need for new more effective and selective drugs to treat these NTDs1516 Currently few antikinetoplastid agents are available although they are still associated with undesired side effects limited efficacy elevated cost and high doses as well as longterm treatment which is often not achieved by patients leading to resistant parasites17 The main drugs currently used to treat Chagas disease are nifurtimox and benznidazole Although they are effective in the acute phase of the disease in the chronic phase they present low efficacy16 Nifurtimox was recently added to the Essential Medicines List EML by WHO being used as a treatment against T b gambiense18 Along with several emerging new active nitroheterocycles targeting T cruzi and T brucei the interest in this chemical class as anti trypanosomal agents has drastically increased141920 Nitric oxide NO superoxide anion O2 hydroxyl and peroxyl radicals are reactive ox ygen species ROS responsible for inducing oxidative stress on cells These species are associated with pathological conditions when Corresponding author Email address edeildojunioriqbufalbr E Ferreira da SilvaJúnior Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry Letters journal homepage wwwelseviercomlocatebmcl httpsdoiorg101016jbmcl2022128930 Received 18 June 2022 Received in revised form 28 July 2022 Accepted 8 August 2022 Bioorganic Medicinal Chemistry Letters 75 2022 128930 2 overproduced disturbing the homeostasis of the intracellular environ ment by reacting unfavorably with cellular macromolecules including DNA proteins and lipids21 Thus nitroaromatic compounds have been shown as potent molecules against a variety of microorganisms although many nitroaromatics have been shown mutagenic but not all of them22 Notoriously the nitrocompounds have demonstrated great impor tance in longstanding studies of their utilization in synthetic organic chemistry Historically nitrocontaining derivatives mainly aromatic ones are essential precursors of explosives and azo dyes Additionally these applications have not been changed although these have been also demonstrated to be valuable reagents for the synthesis of complex targeted molecules23 Furthermore nitrocompounds have been consid ered promising compounds against diverse diseases as well as they have been present in several approved drugs24 In this context it has been demonstrated that the hydroxyl group from nitrophenols can affect the electrochemical changes at the dropping mercury electrode verified by polarographic studies25 In parallel considering that n π transi tions are found at the lowestlying singlet and triplet excited states of simple nitroaromatics26 suggesting that their photochemistry is analo gous to the ketones having similar excited states Morrison and Migdalof decided to study the photochemical hydrogen abstraction by the nitro group27 By using a mixture of onitrotoluene deuterium and dioxane it was verified the presence of a new stretch C D within the infrared spectrum while 10 33 40 and 17 of non mono di and tri deuterated products were identified by mass spectrometry27 The shielding effect of the nitro group was investigated in a study involving 2nitrobenzene derivatives by using a Nuclear Magnetic Resonance NMRbased approach28 Thus it was verified that the chemical shift of the ortho proton from the nitroaromatics relative to the hydrocarbons is not only due to anisotropic effects In accordance with Exner and Kry gowski the nitro group is a substituent par excellence due it could be easily inserted in a molecule and also cause influences the properties of such molecule29 In this context these authors provided an interesting review focused on the quantitative substituent strength electronic and geometric properties of the nitro group and nitrobenzene29 Moreover Sassykova et al30 described several mechanisms of nitro reduction in their review Additionally the nitro group and its derivatives have been Fig 1 Active benzenesulfonylhydrazones 12 and Npropionyl benzenesulfonylhydrazone 3 against NINOA and Inc5 trypomastigote strains of Trypano soma cruzi Fig 2 Nitrofuranbased compounds designed against Trypanosoma cruzi P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 3 investigated for their application in diverse fields of medicinal interest In a study performed by Nisonoff et al31 the nitro group was discussed as a determinant factor for immunologic specificity when investigating interactions of rabbit antibodies prepared against three different hap tens containing nitro groups Recently a nitroalkane analog has been reported as a masked electrophile towards an activesite cysteine res idue which could be promising as a prototype for designing covalent inhibitors32 Herein this review we provide an indepth literature re view showing all studies involving nitro derivatives synthesized so far mainly heterocycles with activity against T cruzi T brucei and different Leishmania species The main goal of this compilation is to allow the readers to have their own conclusions about this great ambiguous chemical group However our opinion is also provided upon the nitro group as a promising Hero or not Villain substituent targeting Trypanosomatidae parasites The following discussion will be focused on nitrocontaining compounds as promising inhibitors target ing different evolutionary forms of Trypanosoma cruzi parasite Nitroaryl inhibitors ElizondoJimenez et al33 designed seven new benzenesulfonylhy drazones and seven Npropionyl benzenesulfonylhydrazones consid ering the inhibitory activities of hydrazone and Nacylhydrazonebased compounds toward the cruzain enzyme from T cruzi Thus these ana logs were evaluated against NINOA and Inc5 trypomastigote strains from Mexico in which their results were compared to the reference drugs nifurtimox and benznidazole According to Fig 1 benzene sulfonylhydrazone 1 was the most potent analog against the NINOA strain which verified that the insertion of the nitro group at the para position of the precursor compound Increased its activity about eight times more On the other hand Npropionyl benzenesulfonylhydrazone 3 was demonstrated to be the most promising analog against Inc5 strain where the ortho insertion in the precursor compound Increased its potency by 30 times more evidencing a fundamental action of this chemical group for the improvement of the activity Furthermore co valent docking studies suggest that the paranitrophenyl group from the analog 1 is oriented to the solventaccessible surface at the active site of cruzain while for compound 3 the orthonitrophenyl group is placed near the Gly66 residue which is important for the inhibition of this macromolecular target Nitrofuran and Nitrothiophene inhibitors Since there are biochemical similarities between tumor cells and pathogenic trypanosomes metabolism catalases and peroxidase en zymes for example Otero et al34 developed four new nitro furylsemicarbazone derivatives and their respective complexes with rhenium Re and ruthenium Ru since the transition metal complexes are used in the development of anticancer compounds Fig 2 These complexes were evaluated against T cruzi Tulahuen 2 strain Com pounds 47 displayed the most promising results being comparable to the reference drug nifurtimox growth inhibition for 50 PGI50 5 µM indicating that these compounds could be used in future studies for the development of trypanocidal agents Subsequently to explore the nitrofuran core as a source of free radicals targeting to increase trypa nocidal activity Cabrera et al35 developed a study reporting 10 new derivatives from this chemical class evaluating the influence of the N alkyl chain extension on the activity So derivatives 8 and 9 showed better activity against epimastigote forms of Tulahuen 2 strain of T cruzi Fig 2 It was observed that these compounds presented better activity than nifurtimox In vivo studies in mice revealed that compound 8 has similar toxicity to the aforementioned drug while analog 9 demon strated significant toxicity Lastly compound 9 presented a similar biological profile to nifurtimox maintaining constant trypomastigote levels in the blood until the end of treatment Romero et al36 synthesized 20 phthalazinylhydrazones attached to different aryl and heteroaryl groups to be potential inhibitors of iron superoxide dismutase FeSOD enzyme since this is a valuable target to be explored in the development of trypanocidal inhibitors FeSOD plays a fundamental role in protect ing the parasite against oxidative damage due to the generation of ROS especially on T cruzi epimastigotes and amastigotes3740 However despite being tested with different aryl and heteroaryl compounds against T cruzi epimastigote forms only compounds 10 and 11 showed significant inhibitory activities Fig 2 Comparatively the benznidazole drug showed an EC50 value of 30 µM with a selectivity index SI of 4 Further investigations focusing on a possible mechanism of action suggest that both compounds can induce oxidative stress reducing mitochondrial dehydrogenase activity and then producing significant ROS levels Lastly the authors suggest that FeSOD inhibition is not the main target Afterward Gomes et al4142 reported two studies exploring the recognized trypanocidal potential of heterocycle 2nitro furans coupled to unsymmetrical metallocene ferrocenyl electron Fig 3 Nitroimidazolebased compounds designed against Trypanosoma cruzi P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 4 donating and cyrhetrenyl electronwithdrawing ligands by using an azine 23diaza13butadiene bisSchiff bases as a linker These com pounds were evaluated against epimastigote forms of T cruzi Dm28c strain in which analogs 1214 showed promising results Fig 2 when compared to nifurtimox IC50 1020 µM In addition the authors indicated that the increase in linker conjugation between metallocenes and 5nitroheterocycle significantly increased IC50 values when compared to their corresponding analogs without such conjugations In another study performed to evaluate the trypanocidal properties of cyrhetrenyl and ferrocenyl ligands Toro et al43 designed and synthe sized four derivatives containing these groups and evaluated them against T cruzi epimastigotes and T brucei trypomastigotes forms In this context compounds 15 and 16 were found to be the most prom ising analogs Fig 2 both being more active than nifurtimox against T cruzi and T brucei species However only analog 16 was more se lective for T brucei parasite than nifurtimox EC50 422 µM Tc SI 21 EC50 356 µM Tb SI 249 EC50 887 µM L6 cells since they were more toxic Finally the authors suggested that these de rivatives are bioactivated by type I nitroreductase enzymes Arias et al19 reported the rational design of a series of 5nitro2furoic acids targeting the trypanothione reductase TcTR from T cruzi in order to interfere with the reduction of NADPH These derivatives Fig 2 have chemical similarities with nifurtimox and benznidazole Further investigations identified two promising analogs 17 and 18 against T cruzi epi mastigotes in which compound 18 was demonstrated to be almost 4 fold more potent than nifurtimox Ki 245 µM IC50 40 µM EC50 272 µM HeLa cells SI 68 although it has equivalent selectivity Finally both of these novel derivatives were identified as reversible and noncompetitive inhibitors of TcTR By using molecular docking the authors suggested that analog 18 binds directly to the TcTRtrypano thione complex which is in agreement with their experimental results Nitroimidazole inhibitors Some studies reporting the efficacy of heterocycle nitroimidazoles can be found in the literature In this context Maya et al44 used the megazol drug 19 as a starting point for their syntheses which has recognized antiparasitic activity although it was initially synthesized aiming the antimicrobial activity45 Then compound 20 was obtained as a prodrug from megazol 19 which undergoes the action of cyto solic peptides in the acetyl region As shown in Fig 3 prodrug 24 showed similar action against T cruzi Tulahuen and Brener epimastigote strains On the other hand the trifluoroacetyl group in compound 21 is poorly hydrolyzed preventing drug releasement This fact may explain why its effectiveness was drastically reduced when compared to mega zol 19 Fig 3 Lastly the action of these nitroimidazole compounds may be associated with oxygen metabolism especially involving try panothione depletion which is processed by an essential enzyme from the parasite Posteriorly by using the bioisosterism approach Carvalho et al46 synthesized and evaluated new azaheterocyclic derivatives based on megazol 19 The modifications involved the replacement of thia diazole with triazole ring due to the electronic similarity of these het erocycles In addition the insertion of a nitro moiety at the C4 position aimed to reduce mutagenic effects without interfering with its antipar asitic activity Bloodstream trypomastigotes from the Y strain Fig 3 Among the synthesized compounds analog 22 was found to be the most promising derivative although it showed reduced activity when compared to megazol 19 with an IC50 value of 99 µM Based on this fact the authors suggested that the nitro group should not be introduced in a different position In another study Buschini et al47 aimed to assess the structureactivity relationship SAR and explore possible mecha nisms of action for megazol analogs So compound 4nitromegazol 23 displays nitro replacement from C5 to C4 position while 5nitroimida zole thiosemicarbazone 24 corresponds to the openthiadiazole het erocycle keeping the nitro group at the C5 position Fig 3 These compounds were analyzed for their capability of inducing in vitro DNA damage on human leukocytes culture where the authors observed oxidative stress on cells treated with megazol 19 while analog 23 did not present such effect It demonstrates that the changes at the nitro position are not biologically significant Additionally it was observed that the genotoxicity of analog 23 occurs by inducing oxidized DNA bases while analog 24 induces DNA damage with higher efficiency compared to 19 megazol acidic hydrazine proton seems to exert a key role on it as it is not observed at its cyclic form thiadiazole ring These studies provide subsidies for the development of new nitroimidazolebased compounds Nitroimidazooxazole inhibitors In view of the antikinetoplastid activity of nitroimidazooxazole de rivatives such as DNDiVL2098 preclinical drug Mathias et al2 eval uated 5substituted 6nitroimidazooxazole derivatives against T cruzi and L donovani parasites Then the authors synthesized 21 novel compounds based on derivative 25 previously reported as a leish manicidal agent although inactive against T cruzi48 Among these molecule 26 containing an ethynyl3methoxyphenyl substituent showed more promising trypanocidal activity being more potent than benznidazole IC50 231 µM On the other hand compound 27 demonstrated more potent leishmanicidal activity although not more than the antifungal drug amphotericin B IC50 018 µM where such results provide support for further studies to explore this chemical class Fig 4 Nitroindazole analogs Aran et al49 investigated nitroindazolebased compounds as a new class of active compounds targeting trypanocidal activity Thus the authors designed and evaluated 15 novel derivatives performing structural modifications at the alkylamine side chain and keeping the nitroindazole core Among the analogs evaluated against epimastigote forms compounds 28 and 29 showed the best activities Fig 5 with a PGI value of 100 as observed for nifurtimox although less potent than this drug which has an IC50 value of 34 µM Compound 28 was more potent than compound 29 suggesting that the aliphatic side chain could be responsible for its activity Fig 5 In addition Boiani et al50 evaluated the mechanism of action of both compounds verifying that analog 28 exerts its action by generating oxidative stress in epi mastigote forms increasing oxygen consumption In contrast Fig 4 Design of nitroimidazooxazolebased compounds with activity against Trypanosoma cruzi amastigotes and Leishmania donovani promastigotes P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 5 compound 29 inhibits oxygen consumption in a concentration dependent manner demonstrating that these derivatives display different mechanisms of action Based on the previous study Rodríguez et al51 described new modifications at the aliphatic side chain of com pound 29 So compounds 30 and 31 present a pyrrolidine and piperidine ring respectively Fig 5 Both compounds showed similar potency epimastigotes from CL Brener clone having no relevant toxicity on macrophages culture Based on electrochemical studies parasite respiration and Electron Spin Resonance ESR the authors suggested that the mechanism of action for these analogs is not related to the production of redoxcycling with molecular oxygen but rather the production of reduced nitro species Muro et al52 reported eight new compounds designed by using a molecular simplification approach along with the extension of the alkyl side chain as well as the ether methyl and benzyl region Among these modifications compounds 32 and 33 were the most promising analogs interestingly having benzyl ether On the other hand compound 32 has only one methyl group at its side chain while compound 33 an ethoxyamine as a substituent Thus both of these compounds were more potent against amastigote and trypomastigote forms as well as less cytotoxic than benznidazole which implies greater selectivity for all parasitic forms These results consolidate the nitroindazole core as a promising nucleus for designing active and selective trypanocidal agents Fig 5 Continuing the studies on this chemical class FonsecaBerzal et al53 modified the 5nitroinda zole core to obtain 5nitroindazolin3one heterocycles functionalizing it at N1 and N2 positions Among the synthesized derivatives com pound 34 was more potent against amastigotes than benznidazole as well as more selective and had similar cytotoxicity Fig 5 Finally the authors suggested that the mechanism of action of this compound should be further investigated which may be related to the induction of oxidative stress in the parasite as well as inhibition of TR enzyme or parasite catabolism Nitrophthalazine inhibitors Olmo et al16 reported a biological study involving four new nitro phthalazine derivatives in order to evaluate their trypanocidal activity After evaluation compound 35 was found to be promising Fig 6 in which it was more active selective and less toxic than benznidazole Fig 5 Nitroindazolebased compounds designed against Trypanosoma cruzi Fig 6 Nitrophthalazine inhibitor of FeSOD active against amastigote forms of Trypanosoma cruzi Fig 7 Promising nitropyrrolebased derivatives active against amastigote form for Trypanosoma cruzi P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 6 IC50 233 µM amastigote IC50 136 µM Vero cell SI 06 Also the authors reported that this new derivative promotes extensive destruction of the parasitic cytoplasm ultrastructural alterations in addition to reducing the damage to cardiac tissue of mice histopatho logical analysis Still no biochemical changes were observed in the liver heart and kidneys This derivative selectively inhibited the anti oxidant FeSOD enzyme Molecular modeling suggests that this inhibi tion occurs via metal coordination with the iron ion at the catalytic site of FeSOD Nitropyrrole inhibitors Recently Mathias et al54 studied the influence of nitropyrrole de rivatives against T cruzi amastigotes This class is known to inhibit the synthesis of sterols CYP5155 For this the authors changed the imid azole heterocycle by pyrrole in addition to functionalizing the aryl re gion with different electrondonating and electronwithdrawing substituents Fig 7 In this context electronwithdrawing substituent metaCF3 in compound 37 showed more potent activity in addition to being noncytotoxic and also in accordance with Lipinskis rule of five On the other hand it presented a maximal effect that was comparatively insufficient to nifurtimox which prevents the evaluation by more enlightening studies Nitrotriazole inhibitors Papadopoulou et al56 reported the structural design of hybrid nitrotriazole derivatives functionalized with another nitrogenous nu cleus such as acridine quinoline and piperazine After synthesizing and evaluating new entities compounds 3840 exhibited the best inhibi tory activities against amastigote forms Fig 8 Such compounds were found to be 8 to 33fold more active than nifurtimox IC50 132 µM evidencing the meaningful potential of these molecules Still they did not show relevant cytotoxicity in addition to compound 40 being substantially selective upon amastigote forms Herein the following discussion will be focused on the nitroheterocyclecontaining derivatives as promising inhibitors target ing different evolutionary forms of Trypanosoma brucei parasite Nitrofuran inhibitors Zhou et al15 synthesized a series of nitrofuran analogs with potent trypanocidal activity against T brucei It was verified that the nitro group in compound 41 is essential for its activity Fig 9 being 2fold Fig 8 Design of nitrotriazole derivatives active against Trypanosoma cruzi amastigotes Fig 9 Nitrofuran analogs with activity against Trypanosoma b brucei T b rhodesiense T cruzi and Leishmania parasites P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 7 more potent than nifurtimox The removal of hydrogen significantly decreases activity against T brucei to IC50 20000 nM without changes significant in its toxicity upon human HeLa cells even at a concentration above 20 µM15 The influence of the nitro group on nitroaromatics coupled to melamine moiety was investigated by Baliani et al22 From the most promising compound 42 Fig 9 it was observed that the replacement of the nitro group with a hydrogen atom on furan ring had significant loss in activity against T b brucei AT1 wild type T b brucei AT1 knockout and T b rhodesiense Also analogously this loss of ac tivity was observed with the thiophen ring The replacement of the nitro group with a nitrile function also leads to the loss of activity against these parasite species These results suggest the importance of the nitro group and also have been shown that more than an electron withdrawing effect is necessary for the activity Complete removal of the nitro heterocycle or replacement of the nitrofuran with a nitrophenol also led to a loss of activity Moreover most nitroheterocycles were less toxic against mammalian cells than melarsoprol which showed an IC50 value of 78 µM against L6 cells and SI of 1300 All these nitrofurans were found to be more active against T cruzi than L donovani Finally compound 42 was able to cure a HATinfected rodent STIB795 model22 Posteriorly compound 42 was evaluated by the same research group and modifications were made at melamine and nitro furan ring Replacement of the nitro group with a carboxylic acid led to a large reduction of activity against T b rhodesiense The carboxylate should be an isostere for the nitro group in terms of its size steric properties and Hbond acceptor properties This implies that the redox properties of the nitroheterocycle are critical for antitrypanosomal activity Replacing the nitrofuran with a nitroimidazole also led to a drastic loss of activity with IC50 values higher than 341 µM against T b rhodesiense57 Chamuvarininbased analogs were evaluated against kinetoplastid parasites T brucei T cruzi and L major as well as their cytotoxicity was assessed on Vero and human HeLa cells The nitro group at the furan ring in compound 43 Fig 9 increased its EC50 values against T brucei and T cruzi when compared to the desnitro compound The replacement of the nitro group with methyl or chloro also decreased the activity against T brucei and T cruzi Relative to L major desnitro compound EC50 78 µM was more active than nitrocontaining compound or methylated EC50 161 µM and chlorinated EC50 500 µM analogs Similarly the desnitro analog of compound 44 Fig 9 exhibited a reduced activity against T brucei T cruzi and L major On the other hand it was observed that com pounds 43 and 44 were more toxic while the desnitro analog of compound 43 presented an EC50 value higher than 500 µM against both line cells58 Nitroimidazole and triazole inhibitors Thompson et al3 reported a drug repurposing study of antitubercular 6nitro23dihydroimidazo21b13oxazoles against NTDs in order to evaluate the role of the nitro group on the activity of this chemical class Compounds 45 and 46 were evaluated against L infantum T cruzi and T brucei Fig 10 Parallelly an analog of compound 45 presented reduced activity against L infantum and T cruzi parasites when its nitro group was removed Regarding their cytotoxicity toward human lung fibroblasts MRC5 it was observed good tolerance for compound 45 and its analog compound 46 Additionally the modification of the nitro group by a bromo atom increased the cyto toxicity suggesting an essential role of the nitro group in antiparasitic activities3 Fig 10 Nitroimidazole and nitrotriazole with activity against Trypanosoma cruzi T brucei and Leishmania infantum Fig 11 Cyrhetrenyl derivative active against Trypanosoma cruzi and T brucei P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 8 Metalcontaining inhibitor Other strategies to find new and more efficient antitrypanosomal agents have involved the utilization of biologically active transition metals coordinated with a bioactive organic molecule In this perspec tive Toro et al18 have investigated a series of bioorganometallic compounds having electrondonor ferrocenyl and electronwithdrawing cyrhetrenyl groups an iminophenyl bridge and a thiophene ring substituted with a nitro group at C4 and C5positions Results demon strate that for these derivatives there is not a linear correlation between nitroreduction and antiT brucei activity Moreover 5Nitrothiophenes are more efficient than their 4nitro analogs as antiT brucei agents Fig 12 Nitrothiadiazole analogs with activity against Leishmania major and donovani species Fig 13 Nitroindazole analogs active against Leishmania braziliensis L amazonensis L infantum and L donovani P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 9 probably due to the generation of nitro radical anions into the biological target Besides ferrocenyl containing the 5nitrothiophenyl ring was less cytotoxic than the 4nitro analog and nifurtimox as well18 Sub sequently Toro et al43 also focused their attention on cyrhetrenyl N acylhydrazone 47 Fig 11 which displayed growth inhibitory prop erties mainly against T brucei being 4 to 10folds more sensitive than T cruzi Cyrhetrenyl derivatives were more toxic on L6 cells than nifurtimox However also they were more potent towards T brucei when compared to nifurtimox43 Finally the following discussion will be focused on the nitroheterocyclecontaining derivatives as promising inhibitors target ing different evolutionary forms of Leishmania parasites Nitrothiadiazole inhibitors Some 5nitrofuranaroylpiperazines and 5nitrothiophenaroylpipera zines were synthesized by BehrouziFardmoghadam et al59 and evalu ated against promastigote forms of Leishmania major MRHOIR75ER strain In general nitrofuran analogs were found to be the most potent compounds with IC50 values ranging from 10 to 13 µM Posteriorly the best compounds were also assessed for their activity against L major amastigotes Then it was verified that compounds 48 and 49 are the most potent molecules Fig 12 against promastigote and amastigote forms respectively However the authors did not provide specific values for the activity of the compound 49 Moreover MTT assays indicated that both compounds exhibit no remarkable toxicity toward murine peritoneal macrophages59 Still the observed differences in anti leishmanial activities for nitrofurans and nitrothiophenes may be due to the reduction of the singleelectrons transfer ArNO2ArNO2 Lastly under aerobic conditions the nitro anion radical reacts with oxygen to form superoxide anion and hydroxyl radical In contrast radical anion can be transformed into the corresponding nitrosoderivative under anaerobic conditions59 The synthesis and in vitro leishmanicidal activity of 5nitroarylthiadiazoles were assessed by MojallalTabatabaei et al60 who reported that 5nitrofuran and 5nitroimidazolecontaining de rivatives exhibit better activity when compared with 5nitrothiophene ones Among all evaluated compounds against L major compound 50 showed a higher antileishmanial activity and selectivity index Fig 12 better than glucantime drug IC50 13661 670 µM 50 mgmL CC50 176075 1219 µM SI 2577 However the antileishmanial potential of this compound is associated with the substituent at the C2 position from the thiadiazole ring A series of megazol derivatives exploring the methoxyl substituted phenylacetyl moiety was synthe sized by Riente et al61 Then it was verified that the 5benzylsulfanyl megazol derivative 51 showed the best results against axenic amasti gotes of L donovani Fig 12 being more potent than the reference drug miltefosine IC50 0268 µM and presenting a SI of 240 However it exhibited higher cytotoxicity on L6 cells61 Nitroindazole inhibitors Boiani et al50 synthesized a series of 5nitroindazoles and evaluated these against in vitro promastigotes of L braziliensis L amazonensis and L infantum Among these compounds derivatives 52 and 53 caused complete lysis of the studied species Fig 13 Compound 52 inhibited oxygen uptake in a concentrationdependent manner and increased oxygen consumption without redoxcycling as well It suggests a different mechanism of action in which the presence of a nitroaromatic group does not allow it to act as a ROS inducer Finally no redoxcycling effect was observed for any of these nitroindazoles Furthermore the effect on the parasitic respiration seems to be related to the amino side chain and not to the nitro group50 Leishmanicidal properties of 5nitro indazoles were also studied against in vitro L infantum and L braziliensis promastigote and amastigote forms by Marín et al62 in which they noted that compound 54 was more active against L infantum intra cellular amastigote forms while compound 55 was more active against L braziliensis intracellular amastigote forms Further com pounds 54 and 55 Fig 13 were proved to be less toxic most effective and selective than glucantime which presented toxicity upon macrophages with a CC50 value of 152 µM SI 0508 while IC50 values of 180 13 242 26 256 17 304 61 µM against L braziliensis promastigotes and L infantum intracellular amastigotes62 Other 5nitroindazole derivatives were synthesized by MartínMontes et al63 where 11 analogs were at least half as toxic as glucantime Compound 56 was more active against L infantum and L braziliensis promastigotes than glucantime which presented IC50 values of 180 31 and 256 17 µM respectively Against L donovani promastigotes glucantime presented an IC50 value of 266 54 µM while compound 57 was more active The glucantime SI was observed between 06 and 08 and its macrophage toxicity with a CC50 value of 1512 10 µM while compounds 56 and 57 presented SI values higher than 23 being less toxic Fig 13 The authors suggested that the activity of these compounds is associated with the intracellular reduction of the nitro group followed by the induction of oxidative stress into the parasites or by the production of highly reactive metabolites capable of reacting with essential biomolecules of protozoa However the relationship between the nitro group and its in vitro activity remains unclear63 The influence of the nitro group on the imidazo12apyridine ring was reported by CasteraDucros et al64 who synthesized 44 compounds of which 23 of them nitrocontaining compounds Among all tested molecules 4 com pounds bearing a nitro group at the C3position from the imidazole12 apyridine ring presented significant antileishmanial activities IC50 20 µM The presence of a halogen atom at the C6position increases the antileishmanial activity Also it was shown that the nitro group is mandatory for conferring activity Thus the replacement of the nitro group with a hydrogen atom reduced the selectivity of the compound against L donovani promastigotes by 25 times less Also it was observed that the presence of the nitro group does not is directly associated with cytotoxicity Thus the lead compound 58 was tested upon L infantum promastigotes and L donovani amastigotes Fig 13 exhibiting good in vitro activities against both of these species being slightly less active toward amastigotes than promastigotes64 Fersing et al65 synthesized a series of analogs of compound 58 and screened them toward L donovani and T b brucei Then it was observed that the replacement of the nitro group with an amino group increases cytotoxicity Besides significantly reduced activity against L donovani promastigotes and T b brucei BSF revealing the key role of the nitro group for the pharmaco phore An indepth evaluation showed that compound 59 displayed better antiT cruzi activity than antileishmanial Fig 13 Moreover its mechanism of action involves its activation by the parasite NTR1 Finally compound 59 was not genotoxic in the comet assay which represents a significant improvement over nifurtimox and benznidazole drugs65 Posteriorly Fersing et al66 performed even more structural modifications to improve the activity of compound 59 by exploring the insertion of a heteroatomic bridge between the imidazopyridine ring and an aryl group at the C8position Similarly higher activity was observed for nitro than aminosubstituted derivatives The nitro de rivative 60 presented low reduction potential E 063 VNHE and higher antikinetoplastid potential Furthermore compound 60 presented activity against L donovani L major and T cruzi being neither mutagenic norgenotoxic and selectively bioactivated by L donovani NTR1166 Nitrodiphenylsulfane inhibitor Delfín et al67 obtained a series of 224dichloro5methylphenyl sulfanyl13dinitro5trifluoromethylbenzene that was evaluated against L donovani axenic and intracellular amastigotes in order to assess their antiparasitic activities It was observed higher activity for those analogs with two nitro groups along with a third electron withdrawing group at the ring B while analogs without nitro groups were completely inactive The antileishmanial activity presented a clear P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 10 correlation with the reduction potential of these compounds in which the most active compound has two nitro groups allowing biological redox activity which leads to ROS generation into Leishmania parasites dissipating the mitochondrial membrane potential Thus compound 61 was identified as the most active analog Fig 14 causing a 28 13 decrease in parasitemia on average when in vivo administered into L donovaniinfected BALBc mice at 25 mgkgday for 5 days while miltefosine led 41 13 67 Nitrofuran inhibitors Some chalcones and chalconelike analogs containing nitrofurans have been studied as antileishmanial agents In this sense Gomes et al68 evaluated their in vitro biological activities upon L infantum and also cytotoxicity on macrophages and Vero cells As result two compounds 62 and 63 demonstrated better results against L infantum amasti gotes and differentiated THP1 macrophages Fig 15 with improved selectivity than amphotericin B EC50 CC50 and SI values of 19 98 µM and 52 respectively Besides structureactivity relationship SAR analyses revealed that the presence of a nitrofuran ring is favorable to their biological activity against this parasite68 Romero et al69 evaluated the influence of the nitro group on nitrofuran hydrazones as potent agents against L braziliensis Among them three nitrosubstituted compounds showed the most significant inhibition of the promastigote proliferation of the parasite with PGI50 values ranging from 5814 to 8846 at 20 µM concentration compared to miltefosine with PGI50 6778 Compounds without the nitro group demonstrated weak antileishmanial activities EC50 20 µM with low PGI50 values 40 at 20 µM evidencing the important role of nitro substitution in the anti leishmanial activity The researchers established that substitution of a specific arylidene group by a nitroheteroarylidene group linked to hydrazone increases significantly the antileishmanial activity The nitro substitution arylidene system increases the antileishmanial activity with respect to their arylidene phthalazineanalogs and ortho or metanitro at arylidene system represents a significant loss of their biological activity69 Among the synthesized compounds analog 64 was the most promising candidate Fig 15 It is believed that its antileishmanial activity is associated with the highly conjugated arylheteroaryl hydrazone moiety Also it was observed that the nitro group at C4 and C5positions of aryl and heteroaryl moieties facilitates an optimal πelectron conjugation from hydrazinyl group to nitro group explaining the direct relationship between the electronic nature of this compound and its antileishmanial activity It suggests that the nitro group can be involved in an electron transfer reaction from the redox metabolism of the parasite The lowest antileishmanial activity was observed among derivatives having electrondonating groups halogens unsubstituted and metanitro groups Upon BMDM cells compound 64 exhibited a moderate in vitro toxicity but still with good selectivity being much more destructive to the parasitic form than host cells Still it presented good activity against L braziliensis amastigotes Furthermore its mechanism of action is probably associated with the induction of oxidative stress generated by bioreduction of the nitro group and the production of nitric oxide on infected macrophages69 Nitroquinolinone inhibitor A series of 8nitroquinolin21Hone derivatives have been studied as NTRbioactivated antikinetoplastid molecules Recently Pedron et al70 identified compound 65 Fig 16 with low cytotoxicity on human HepG2 cells and activity against L donovani promastigotes and amastigotes L infantum axenic amastigotes and T brucei trypomasti gotes The research team focused on the influence of the redox potentials toward L infantum in which was observed that the lactam function combined with a nitro group at the C8position significantly increases this property When the nitro group is moved to C5 or C6positions its redox potential is lost The improved antileishmanial activity of com pound 65 was associated with an intramolecular hydrogen bond be tween the lactam ring and the nitro group which increases the redox Fig 14 Nitrodiphenylsulfane analog with in vitro and in vivo activities against Leishmania donovani Fig 15 Nitrofuran analogs with activity against Leishmania infantum and L braziliensis Fig 16 Nitroquinolinone derivative with activity against Leishmania donovani L infantum and Trypanosoma brucei P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 11 potential value by 03 V However the absence of the nitro group was accompanied by a loss of activity70 Nitrotriazole inhibitors A series of 3nitro1H124triazolebased amides and sulfonamides were screened as potential antitrypanosomal agents Among these 29 compounds demonstrated significant activities against T cruzi intra cellular amastigotes exhibiting IC50 values ranging from 28 nM to 372 µM without meaningful toxicity17 Also it was observed moderate ac tivity of compound 66 Fig 17 against T b rhodesiense trypomasti gotes T b brucei trypomastigotes and L donovani Additionally Papadopoulou et al71 synthesized and evaluated 2nitro1Himidazole based amides with propanamides aryloxyphenyl and nitrotriazole based acetamides as antitrypanosomal agents Then compound 67 Fig 17 a 3nitrotriazolebased derivative was found to be extremely potent as an antiT cruzi agent while 2nitroimidazole analogs present moderate activity against T cruzi amastigotes Similarly several prop anamides exhibited activity against L donovani although less potent than their corresponding acetamide analogs In contrast these analogs demonstrated great activity toward a T cruzi murine model71 Conclusions The nitro group is extremely versatile and has been broadly used in studies involving Trypanosomatidae parasites in special T cruzi T brucei and Leishmania spp In this context the nitrofuran and nitro indazole analogs have been extensively explored to design and develop more active compounds against these parasites However nitrofurans have displayed great chemical diversity in the literature including even their coordinated ruthenium and rhenium metallocene complexes Moreover nitrofurans demonstrated promising in vitro and in vivo effects in studies involving T cruzi being more effective than nifurtimox and benznidazole drugs Still these derivatives have been associated with the capability of generating ROS or reducing NADPH into T cruzi epi mastigotes and amastigotes via inhibition of FeSOD and TcTR enzymes respectively Concerning the nitroindazole analogs the second more explored chemical class these seem also to induce oxidative stress increasing the oxygen consumption in T cruzi epimastigotes In T b brucei and T b rhodesiense these derivatives can increase the levels of reduced species of nitro compounds being more active than nifurtimox Besides nitroindazoles have demonstrated in vivo activity in T brucei infected rodent models This chemical class of active compounds has been broadly studied against different Leishmania species It was observed that these analogs can inhibit the oxygen uptake in a concentrationdependent manner increasing the oxygen consumption without redoxcycling in promastigotes of L braziliensis L amazonensis and L infantum Additionally some studies suggest that nitroindazoles exhibit fewer toxic effects than glucantime in which the nitro group is not directly associated with their toxicities In some cases the nitro group seems not to be related to the induction of reactive species as the main mechanism of action of compounds addressed to Trypanosomatidae parasites Similarly this chemical group is not directly associated with the increase in the toxicity of some nitrocontaining analogs as well since some nitrocontaining derivatives have demonstrated better tolerance than reference drugs in cytotoxicity assays In addition it is evident that the nitro group can induce improvements in the activity of compounds allowing those to interfere with critical enzymes of these parasites such as FeSOD and TR by generating reactive oxygen and nitrogen species Then the remaining question for this context is Could the nitro group be a hero Well after a critical analysis of all data re ported herein the answer is Yes surely It is clear that the nitro group has provided interesting and promising results against such parasites in which its benefits outweigh the harm justifying the presence of this chemical group in reference drugs such as nifurtimox benznidazole T cruzi fexinidazole T brucei as well as the prototype DNDi0690 Leishmania Regarding the perspectives for this topic there is a big challenge to overcome The nitro group can be a hero but when combined with the correct nucleus aromatics or heterocycles But this fact leads to the next question What would be the best chemical core to use Well it is believed that nitrofuran core has demonstrated versatile applications against these parasites However the nitro group can be even further explored to build large chemical libraries of nitro containing compounds increasing the chemical diversity of molecules potentially active against these NTDs Lastly this strategy will increase the chances to obtain more effective lead compounds which may become a drug in the future Funding sources This research did not receive any specific grant from funding agencies in the public commercial or notforprofit sectors Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper Data availability No data was used for the research described in the article Acknowledgments The authors thank the Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior CAPES Fundaçao de Amparo a Pesquisa do Estado de Alagoas FAPEAL and the National Council for Scientific and Tech nological Development CNPq for their support to the Brazilian Post Graduate Programs Fig 17 Nitrotriazole analogs with activity against Leishmania donovani Trypanosoma brucei rhodesiense and T cruzi P Fernando da Silva SantosJúnior et al Bioorganic Medicinal Chemistry Letters 75 2022 128930 12 References 1 Fersing C Basmaciyan L Boudot C et al ACS Med Chem Lett 20191034 2 Mathias F Cohen A Kabri Y et al Eur J Med Chem 2020191 112146 3 Thompson AM OConnor PD Blaser A et al J Med Chem 2016592530 4 Aronson NE Joya CA Infect Dis Clin North Am 201933101 5 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Introdução à Química Farmacêutica Prof Dr Paulo Fernando Júnior Alunoa Roteiro da a Prova 1 AB1 1 a A partir da leitura do artigo em anexo selecione uma molécula para trabalhála nessa prova compartilhem entre si para não haver moléculas repetidas além disso não serão aceitas moléculas que estejam ilustradas no artigo com seu respectivo receptor Com base nessa molécula crie 4 novos derivados a seu critério em que pelo menos 2 desses novos derivados possuam 2 centros quirais cada indicar as respectivas configurações RS 1 b Com base nos conhecimentos relatados em aula crie um receptor biológico com 4 tipos de interações intermoleculares e encaixe todas as moléculas do item 1 Qual composto demonstrou mais interações Explique detalhadamente Ex 2 No site httpwwwswissadmech insira cada uma das 4 moléculas indicando numa tabela pelo menos 5 diferentes propriedades físicoquímicas e de 3 de metabolismo obtidas por meio dos cálculos deste programa Discuta como as alterações de cada molécula podem ter promovido tais diferenças bem como se as mesmas se enquadram ou não na regra de Lipinsk Tutorial a Desenhe a molécula de acordo com os grupos funcionais que você planejou b Obtenção dos dados 3 a O Dimenidrinato Dramin também conhecido como Bdimetilaminoetil benzoidrol éter 8cloroteofilinato é indicado para prevenir náuseas vômitos e tonturas causadas por cinetose Esse fármaco foi descrito pela primeira vez na literatura em 1949 e patenteado em 1950 As primeiras pesquisas sobre o este fármaco se concentraram em seu papel como anti histamínico para urticária o tratamento do enjoo foi uma descoberta acidental DRUGBANK 2021 Sabendo disso você agora está responsável por realizar alguns estudos em torno dessa molécula para isso será necessária a aplicação dos seus conhecimentos adquiridos até agora na disciplina de Introdução à química medicinal Dimenidrinato Dramin Tabela Log P constantes a Avalie a solubilidade deste fármaco por meio do cálculo do LogP b De acordo com a regra de Lipinski esse fármaco possui uma boa biodisponibilidade oral 3 b Amobarbital pertence á classe dos barbitúricos e possui propriedades hipnóticas e sedativas A reação abaixo mostra seu comportamento em solução exemplificado também pelo gráfico 1 que demostra a ionização sofrida pelo fármaco em diferentes pH Diante do exposto responda Qual Pka do Amobarbital a 5 b 6 c 7 d 8 e NDA Gráfico 1 4 a Pesquise um fármaco a sua escolha e descreva todo o seu processo de síntese relatando método solventes reagentes tipo de síntese rota sintética etc Compartilhem entre si para não haver compostos repetidos a Breve exemplo Day After Day Still freeman in my mind So many days Waiting to see the sign Dont stop singing everywhere Just try to live from day to day The time is going by far Away Toujours la même histoire vous sentez La chose qui srépète le temps est bien trop pressé Toujours la même histoire vous tremblez Stop le stress nos maladresses lhorloge continue de tourner Dub Inc Boa prova a todos as Good test everyone Bon test a tous