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In this research, the synthesis, photochemistry, and computational study of new cis- and trans-isomers of amino-thienostilbenes is performed to test the efficiency of their production and acid resistance, and to investigate their electronic structure, photoreactivity, photophysical characteristics, and potential biological activity. The electronic structure and conformations of synthesized thienostilbene amines and their photocyclization products are examined computationally, along with molecular modeling of amines possessing two thiophene rings that showed inhibitory potential toward cholinesterases. New amino-styryl thiophenes, with favorable photophysical properties and proven acid resistance, represent model compounds for their water-soluble ammonium salts as potential styryl optical dyes. The comparison with organic dyes possessing a trans-aminostilbene subunit as the scaffold shows that the newly synthesized trans-aminostilbenes have very similar absorbance wavelengths. Furthermore, their functionalized cis-isomers and photocyclization products are good candidates for cholinesterase inhibitors because of the structural similarity of the molecular skeleton to some already proven bioactive derivatives.

U ovom završnom radu provedena je sinteza i spektroskopska karakterizacija novih supstituiranih derivata amino-heterostilbena kao potencijalno biološki aktivnih molekula. Sinteza novih amino-heterostilbena provedena je u nekoliko koraka. Wittigovom reakcijom dobiveni su cis- i trans-heterostilbeni iz tiofen-2-karbaldehida i 1-brom-2-(4-klorbenzil)fosfonijeve soli, koji su u sljedećem koraku reakcijom Buchwald-Hartwigovog aminiranja prevedeni u spojeve 2-6. Novonastali spojevi pročišćeni su uzastopnom kolonskom i tankoslojnom kromatografijom pomoću preparativnih ploča obloženih silikagelom. Dobiveni produkti uspješno su izolirani i okarakterizirani spektroskopskim metodama. Prilikom izrade ovog završnog rada ukupno je dobiveno deset amino-heterostilbena, te pet elektrociklizacijskih produkata. In this final work, the synthesis and spectroscopic characterization of new substituted derivatives of amino-heterostilbene were performed as potential biologically active molecules. The Wittig reaction gave cis- and trans-heterostilbenes from thiophene-2-carbaldehyde and 1-bromo-2-(4-chlorobenzyl)phosphonium salt, which were converted into compounds 2-6 by the Buchwald-Hartwig amination reaction in the second step. The newly formed compounds were purified by repeated column and thin-layer chromatography using preparative plates coated with silica gel. The obtained products were successfully isolated and characterized by spectroscopic methods. During the preparation of this work, a total of ten amino-heterostilbenes and five electrocyclization products were obtained.

S ciljem pronalaska novih potencijalnih inhibitora kolinesteraza sintetizirani su novi heterostilbenski derivati 4-pirona. Wittigovom reakcijom sintetizirane su cis- i trans- heterostilbenske strukture iz određenih aldehida i fosfonijevih soli 4-pirona. Ukupno je dobiveno i izolirano deset heterostilbenskih 4-pironskih derivata. Svi produkti pročišćeni su kolonskom kromatografijom, a strukture su im okarakterizirane i potvrđene 1H, 13C i 2D NMR spektrima te UV i IR spektrima. Kristalne strukture dva pironska heterostilbena dodatno potvrđuju strukturu i pakiranje dobivenih spojeva, a ispitano je i njihovo kompleksiranje s biometalima kao i utjecaj temperature na kemijske pomake u NMR spektrima. In order to find new potential cholinesterase inhibitors, new heterostilbene derivatives of 4-pyrone were synthesized. The Wittig reaction yielded cis- and trans-heterostilbene structures from certain aldehydes and phosphonium salts of 4-pyrone. A total of ten 4-pyrone heterostilbene derivatives were obtained and isolated. All products were purified by column chromatography, and their structures were characterized and confirmed by 1H, 13C and 2D NMR spectra and UV and IR spectra. The crystal structures of two of them further confirm the structure and the packing of the obtained compounds. Additionally their complexation with biometals has been investigated as well as the influence of the temperature on the chemical shifts in the NMR spectra.

Photochemical reactivity in the Z-E isomerization for two heterostilbene derivatives containing 1,2,3-triazole unit were investigated theoretically and experimentally by irradiation experiments, fluorescence and laser flash photolysis (LFP). The molecules were designed to probe the effect of the para-nitro group in 1 on the photochemical E-Z pathways, as well as to investigate the steric effect of the ortho-methyl group in 2. The quantum yield for the Z → E isomerization for both cis-isomers is 0.42, and for the E → Z is somewhat lower 0.16 and 0.12, respectively. Furthermore, fluorescence measurements for the ortho-methyl derivative indicated that the Z → E isomerization takes place in an adiabatic reaction on the potential energy surface of the S1 state. On the contrary, the para-nitro derivative undergoes the Z → E isomerization via a triplet excited state, which was detected by LFP. For both cis- and trans-isomers of the nitro derivative a transient was detected absorbing with a maximum at 520 nm, which was assigned to the triplet excited state of the trans-isomer. All experimental observations were corroborated by computations. The stationary points were computed at the PBE50/6-31++G** level of theory, whereas potential energy surfaces were obtained by linear interpolation and computations at the SF-TDDFT/PBE50/6-31++G** level of theory. The mechanistic investigation presented gives insight in the fundamental and simple Z → E isomerization and provides new findings which are important in the rational design of different photoreactive diarylethene derivatives used in different fields of science.

The inhibition of AChE and BChE by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by sequence of three reactions in very high yields. The expected targeted products were pure cis- and trans-isomers of syn- and anti-oximes containing different substituents bound in the para- position of the benzene ring.1 Eight trans, anti- and trans, syn-isomers of oximes were tested as reactivators of nerve-agent- inhibited AChE and BChE. Four derivatives reactivated cyclosarin- inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin- inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, these compounds present a new class of oximes with the potential for further development of CNS- active therapeutics in OP poisoning. This is the first study to show the potential of thienostilbene oximes as therapeutics in OP poisoning, and it seems that further design of the compounds e.g., with amide, OH, mono- and dimethylamino groups, or triazole ring, could provide a new platform for further antidote and scavenger development for exposure to organophosphates.

Oximes, the symptomatic drugs currently were used as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the treatment of neurological disorders such as Alzheimer’s and Parkinson’s disease. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by sequence of three reactions in very high yields. Eight trans, anti- and trans, syn-isomers of oximes were tested as reactivators of nerve-agent- inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti- and trans,syn-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

S ciljem pronalaska novih potencijalnih reaktivatora enzima acetilkolinesteraze inhibiranog djelovanjem organofosfornih živčanih agenasa sintetizirani su novi derivati 3-tienostilbenskih oksima. Wittigovom reakcijom sintetizirani su cis- i trans-heterostilbeni iz 3-tienilnog aldehida i p-supstituiranih fosfonijevih soli kao polazne strukture s ciljem prevođenja u oksim. Tri odabrane soli kao supstituente na benzenskom prstenu sadržavale su metilnu skupinu, klor i cijano-skupinu. Heterostilbeni su funkcionalizirani Vilsmeierovim formiliranjem čime su dobiveni karbaldehidi. Karbaldehidi su u zadnjem sintetskom koraku prevedeni u oksime reakcijom oksimiranja uz hidroksilamin hidroklorid kao reagens. Ukupno je dobiveno i izolirano dvanaest oksima od kojih su četiri oksima s metilnim supstituentom i dva oksima s cijano-supstituentom dobiveni u dovoljnoj količini za biološka istraživanja reaktivacije enzima acetilkolinesteraze. Svi međuprodukti i produkti pročišćeni su kolonskom kromatografijom, a strukture su im okarakterizirane i potvrđene 1H i 13C NMR spektrima. In order to find new potential reactivators of the enzyme acetylcholinesterase inhibited by the organophosphorus nerve agents, new derivatives of 3-thienostilbene oximes were synthesized. Wittig reaction yielded cis and trans heterostilbene isomers that were synthesized from 3-thienyl aldehyde and p-substituted phosphonium salts as the starting structures with the aim of conversion to the oxime. The three selected salts contained methyl, chlorine and a cyano group as a supstituent on the benzene ring. Heterostilbenes were functionalized by Vilsmeier formylation to give carbaldehydes. In the last synthetic step, the carbaldehydes were converted to oximes by an oximation reaction with hydroxylamine hydrochloride as a reagent. A total of twelve oximes were obtained and isolated of which four oximes with methyl substituent and two oximes with cyano substituent were obtained in sufficient quantity for biological studies of acetylcholinesterase enzyme reactivation. All intermediates and products were purified by column chromatography and their structures were characterized and confirmed by 1H and 13C NMR spectra.

On the basis of earlier results with furan and thiophene derivatives of benzobicyclo[3.2.1]octadiene, photocatalytic oxygenation of novel furo- and thieno heterostilbenes with water-soluble manganese(III) porphyrins offered suitable possibilities to study their reactivities and reaction pathways depending on the heteroatom and the catalyst charge. The experiments were carried out in two reactors types (batch and microflow) to investigate the geometric effects. NMR spectroscopy, GC, and UPLC/MS analyses were applied for identification and quantification of the products. As our results indicated, the 2-thienyl and the common p-tolyl groups in the starting compounds remained intact due to their stronger aromaticity. Hence, the thieno derivative underwent oxygenation only at the open-chain part of the molecule, and the rates of its reactions were much lower than those of the furyl analogue. The less stable furan ring was easily oxygenated, its products with highest ratios were 2-furanon derivatives. Epoxide formation occurred at the open-chain parts of both substrates preferably by the anionic catalyst. Nevertheless, the conversion rates of the substrates were higher with the cationic porphyrin, according to electrophilic attacks by photogenerated Mn(V)=O species. Additionally, the reactions were significantly faster in microflow reactors due to the more favorable circumstances of mass transfer, diffusion, and light penetration.

The synthesis, photoreactivity, and spectroscopic characterization of novel 1,2,3-triazole di-heterostilbenes bearing various aliphatic and aromatic substituents on the triazole rings were thoroughly explored. By introducing triazole rings into the o-divinylbenzene moiety, compared with the 2-furyl and 2-thienyl heteroanalogues, these compounds did not show any photochemical reactivity toward intramolecular cycloaddition reactions or electrocyclization processes. The research is further extended to the more in-depth examination of photochemical and photophysical characteristics of the investigated triazolo-stilbenes to explain the lack of reactivity in intramolecular photochemical cyclizations by configuration and substituent effects. Conformations of synthetically obtained novel triazoles are examined by Density Functional Theory (DFT). The time dependent-DFT approach was employed to obtain additional insight into the properties observed with UV/Vis spectroscopy. The frontier orbital energy was computationally investigated to determine the influence of cis–trans isomerism and the nature of substituents on the spectroscopic properties of the triazoles. Along with our previous studies of similar compounds containing furan and thiophene, respectively, this study shows that introducing various heteroaromatic rings induces diverse photochemistry and photophysics due to the conformational changes and change in electronic distribution within the molecular system.

U cilju proučavanja djelovanja oksimskih derivata heterostilbena kao reaktivatora kolinesteraza sintetizirani su novi spojevi 15 – 21. Dobivanje željenih spojeva započinje Wittigovom reakcijom kojom su sintetizirani heterostilbeni 1 – 7, koji su Vilsmeier-Haackovim formiliranjem prevedeni u aldehide 8 – 14. Na njima je provedena reakcija u cilju dobivanja oksimskih derivata 15 – 21, koji do sada literaturno nisu poznati. Očekivani produkti bili su cis- i trans- izomeri spojeva 15 – 21, s nizom različitih supstituenata vezanih u para- položaju benzenskog prstena. U konačnici, u svakoj provedenoj reakciji dobivanja oksima nastala su četiri izomera, s obzirom na konfiguraciju dvostruke veze ugljika, te s obzirom na konfiguraciju dvostruke veze između ugljika i dušika oksimske skupine. Svaki dobiveni oksimski derivat 15 – 21 može zauzeti četiri različita izomerna oblika: cis, syn-, trans, syn-, cis, anti-, trans, anti-. Svi novi spojevi okarakterizirani su spektroskopskim metodama, a za one dobivene u dovoljnoj količini bit će ispitana reaktivacijska aktivnost prema humanim enzimima AChE i BChE. For the purpose of studying the effect of oxime derivatives of heterostilbene as a cholinesterase reactivators, new compounds 15 – 21 were synthesized. Starting ompounds 1 – 7 were synthesized using the Wittig reaction, and they are converted to the aldehydes 8 – 14 by Vilsmeier-Haack formylation. In order to obtain previously unknown oximes 15 – 21, oximation was carried out. The expected products were the cis- and trans- isomers of compounds 15 – 21, which contain different substituents bound in the para-position of the benzene ring. Finally, in each reaction of oxime formation, four isomers were obtained, considering to the configuration of the carbon-carbon double bond, and to the double bond between the carbon and nitrogen of the oxime group. Each obtained oxime derivative 15 – 21 can take four different isomeric forms: cis, syn-, trans, syn-, cis, anti-, trans, anti-. All new compounds were characterized by spectroscopic methods, and for those obtained in sufficient quantities, the reactivation activity against human enzymes AChE and BChE will be tested.

A new synthetic approach is presented for the synthesis of naphthoxazoles and fused heterobenzoxazoles. The starting 5−(aryl/furyl/thienyl/pyridyl ethenyl)oxazoles are prepared from the corresponding α, β−unsaturated aldehydes using Van Leusen reagent in very good yields and are transformed into naphthoxazoles and fused heterobenzoxazoles on irradiation under aerobic conditions and in the presence of iodine. All new compounds are characterized by spectroscopic methods. As the starting aldehydes for the reactions with TosMIC were all in trans configuration the obtained 5 − aryl/heteroaryl − ethenyloxazoles retained the trans configuration which is clearly seen from the coupling constants of ethylene protons (J = 16 Hz) in 1 H NMR. It is interesting that H − 2 and H − 4 oxazole protons of all Ar/Het − ethenyloxazole derivatives appear at the same δvalues, around 7.8 and 7.1 ppm, respectively. The two ethylene protons were also found in all examples in a similar narrow region as two doublets at 6.7 − 7.0 and 6.9 − 7.1 ppm, respectively.