Title
Imino derivatives of carbonothioic dihydrayides and cinnamic acids amides : structure-activity relationship studies
Creator
Assaleh, Mohamed H., 1982-
CONOR:
100206601
Copyright date
2022
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Autorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
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Language
Serbian
Cobiss-ID
Theses Type
Doktorska disertacija
description
Datum odbrane: 15.07.2022.
Other responsibilities
Academic Expertise
Tehničko-tehnološke nauke
University
Univerzitet u Beogradu
Faculty
Tehnološko-metalurški fakultet
Alternative title
Имино деривати дихидразида тиоугљене и амида циметних киселина : корелације структуре и активности
Publisher
[M. Assaleh]
Format
XI, 140 str.
description
hemical sciences - Organic chemistry / Хемијске науке - Органска хемија
Abstract (en)
Two series of compounds were synthesized in this PhD thesis: Salicylaldehyde (sal) and 2-
Acetylpyridine (2ap) mono- and bis-(thiocarbohydrazones), m-TCH and b-TCH, respectively (first
series), and cinnamic acids amides (second series), in overall twenty eigth compounds.
All synthesized compounds are characterized using both experimental and theoretical methods.
Experimental techniques include FT-IR, NMR and UV-Vis spectroscopy, as well as elemental
analysis used for structural and purity characterization. The use of UV-Vis and NMR spectroscopy,
and theoretical (“quantum chemical”) calculations was applied to get a deeper insight into
experimental data related to the ratio of Z/E isomer and thion/thio tautomerism versus related
antioxidant activity induced by water addition to dimethyl sulfoxide (DMSO) TCHs solution. Water-
induced breakage of intra-molecular hydrogen bond in mono- and bis(salicylaldehyde)TCH, i.e. [(2-
hydroxyphenyl)methylene]carbonothioichydrazide, m-TCHsal, and 2,2'-bis[(2-
hydroxyphenyl)methylene]carbonothioic dihydrazide, b-TCHsal, lead to E to Z isomerization. Good
accordance of experimental data, from 1H and 13C NMR and 2D NOESY spectra, and theoretical
ones, obtained using GIAO/B3LYP-6-311G++(d,p), with respect to geometrical E:Z isomer ratio, e.g.
81:19 for m-TCHsal was obtained. Destabilization of the ground state lowers bond dissociation
enthalpy (BDE) for 11 kcal/mol, and as consequence leads to more extensive electron spin
delocalization in Z-isomers.
Additionally, 2-acetylpyridine based TCH, i.e. E-[1-(2-pyridinyl)ethylidene]-carbonothioic
dihydrazide, m-TCH2ap, and 2,2'-bis[1-(2-pyridinyl)ethylidene]carbonothioic dihydrazide, b-
TCH2ap, are susceptible to thione/thiol tautomerism as a phenomenon which contributes to lower
BDE and effectiveness of the hydrogen transfer to DPPH∙ is facilitated in that manner. Analogously,
experimental and theoretical results confirmed the shift of m-TCH2ap and b-TCH2ap to thiol form by
water addition. These data were observed from the calculation of ZPE-corrected energy, enthalpy,
BDEs, and the extent of radical spin delocalization of the isomers of studied compounds. Results
indicate that increased participation of the thiol group in thiol/thion equilibria highly contributes to
increased radical scavenging activity of compounds m-TCH2ap and b-TCH2ap. The spin density
delocalization in thiol form of m-TCH2ap and b-TCH2ap occupy almost entire structure. Opposite is
true for thione radicals. This fact is observed by a significant increase of antioxidant activity of all
compounds, e.g. 0.67 for b-TCH2ap in DMSO and 0.13 in DMSO:H2O = 4:1 (IC50 in mM).
A second part includes the synthesis of twenty four cinnamic acid amides (cinnamamides) with
TCHs pharmacophore, synthesized by coupling of acid chlorides: cinnamic, 3-chlorocinnamic, 4-
chlorocinnamic and 4-methoxycinnamic acid with m-TCH containing: pyridine-2-yl, salicyl, 8-
hydroxyquinoline-2-yl and 2-acetyl moiety. Synthesized compounds have been investigated for their
biological properties in terms of anticancer and antimycobacterial activity. Analogous synthesis was
applied with 3-hydroxycinnamic acid using the same set of m-TCH and HATU coupling agent.
Finally, amides based on Caffeic and Ferulic acids with m-TCH containing pyridine-2-yl and salicyl
moieties were synthesized in the same manner, and used for study of their antioxidative potential.
Within assessment of compounds’ ability to induce death of malignant cells, five human cell lines
were treated over 24 h: colorectal adenocarcinoma (LoVo), ovarian adenocarcinoma (SkOV-3), lung
adenocarcinoma (A549), breast adenocarcinoma (MCF-7) and pancreatic adenocarcinoma (AsPC-1).
Obtained results showed that A549 cells were the most sensitive to tested treatments, whereas
compounds 3-ClCimTCHsal and 4-ClCimTCH8OH2qu revealed superior activity and were set as the
focus of a further anticancer investigation. Although 4-ClCimTCH8OH2qu acted as a more powerful
inducer of apoptotic death than 3-ClCimTCHsal, both compounds in A549 cells stimulated cell cycle
arrest at the G0/G1 phase, as well as activation of the intrinsic caspase cascade. A notable difference
ii
in mechanisms of their pro-apoptotic activity refers to the ability of 4-ClCimTCH8OH2qu to strongly
arouse generation of superoxide anion in mitochondria, which was not seen in A549 cells subjected
to 3-ClCimTCHsal. Evaluation of their antimigratory properties demonstrated that compound 3-
ClCimTCHsal significantly inhibited mobility of A549 cells, which was not recorded in samples
treated with 4-ClCimTCH8OH2qu. Finally, powerful cytotoxicity of 4-ClCimTCH8OH2qu on HaCat
(human keratinocytes) and HepG-2 (hepatocellular adenocarcinoma) cells that were employed as
models for skin and liver toxicity, uncovered that this compound has disadvantageous toxicity profile.
On the contrary, 3-ClCimTCHsal had only a moderate impact on the vitality of HaCaT cells, and
therefore proved as suitable for future investigations of its anticancer properties. The capacity of
compounds to interfere with proliferation and survival of Mycobacterium tuberculosis (Mtb), which
is a pathogen responsible for the development of tuberculosis (TB), was assessed on three strains
from clinical isolates, each comprising a specific resistance genotype: Mtb-InhRif-S with no specific
mutations associated with resistance to isoniazid (INH) and/or rifampicin (RIF), Mtb-Inh-R harboring
specific mutation for resistance to RIF, and Mtb-Rif-R holding specific mutation associated with
resistance to INH. After 6 days of incubation with investigated drugs, with INH and RIF as positive
controls, CimTCH8OH2qu was the only one that successfully reduced Mtb viability for more than 90
% in all three treated strains. Moreover, compound CimTCH8OH2qu did not induce the death of HepG-
2 cells, which indicates its favorable hepatotoxicity profile compared to current therapeutic options
for the treatment of TB.
A third part of the present study included an antimicrobial study of three series of cinnamic acid
amides: cinnamic, 4-chlorocinnamic and 4-methoxy cinnamic acid and m-TCH containing: pyridine-
2-yl, salicyl, 8-hydroxyquinoline-2-yl, and 2-acetyl moiety. The antimicrobial study against
Enterococcus cloacae ATCC13047, Staphylococcus aureus NCTC 6571, Klebsiella pneumoniae
ATCC 13883, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa NCTC 10662, and
Escherichia coli ATCC 1175 was performed. Some of the cinnamic amides showed good in vitro
activity against all strains tested, i.e. amides based on cinnamic, 4-chlorocinnamic and 4-methoxy
cinnamic acid and m-TCH2ap, i.e. CimTCH2ap, 4-MeOCimTCH2ap и 4-ClCimTCH2ap. Moreover,
all compounds showed acceptable to high activities with respect to A. baumannii, a widely spread
opportunistic pathogen in hospitals. The most active derivative was 4-MeOCimTCH2fp, with MIC50
value of 10.4 (μmol). Additionally, in order to establish relation of structure and antibacterial activity
against A. baumanii an alignment-independent 3D QSAR model was developed for the identification
of pharmacophoric hotspots. In order to rationalize antimicrobial mechanism, the iron chelation
capability of synthesized compounds was determined using UV-Vis spectrophotometric method. Due
to the presence of strong donor sites the synthesized compounds showed strong iron chelating ability
by creating complexes with the stability constant in the range from 107 to 109. Determined stability
constants indicate that interaction of iron and synthesized compounds is an important step in the
reaction pathway of antimicrobial activity against A. baumanii.
Abstract (sr)
У овој докторској дисертацији синтетисане су две серије једињења: салицилалдехид
и 2-ацетилпиридин моно- и дитиокарбохидразони, TCH (прва серија), и амиди циметних
киселина (друга серија), укупно двадесетосам једињења.
У првом делу дисертације, применом експерименталних и теоријских метода су
окарактерисана сва синтетисана једињења. Експерименталне технике су укључиле: FT-
IR, NMR и UV-Vis спектроскопију, као и елементалну анализу. Употреба UV-Vis и NMR
спектроскопије и теоријских прорачуна примењена је да би се добио бољи увид у
експерименталне податке који се односе на однос Z/E изомера и повећану
антиоксидативну активност након додатка воде у раствор диметил-сулфоксида (ДМСО)
TCHs. Вода раскида интрамолекуларне водоничне везе у [(2-хидроксифенил)-
метилен]карботиохидразид, m-TCHsal и 2,2'-bis[(2-хидроксифенил)метилен]карботио-
дихидразид, b-TCHsal, који доводе до E и Z изомеризације. Резултати из 1H и 13C NMR и
2D NOESY спектара и теоријских израчунавања, добијених коришћењем GIAO/B3LYP-
6-311G++(d,p) базиз сета, указују на 81:19 однос E:Z изомера за m-TCHsal. Такође,
израчунато је да услед дестабилизације основног стања, енталпија дисоцијације везе
(енгл. Bond Dissociation Energy, BDE) је мања за 11 kcal/mol, а делокализација спина
електрона у Z -изомерима је значајнија.
Поред тога, Е-[1-(2-пиридинил)етилиден]карботиохидразид, m-TCH2ap, и 2,2'-bis[1-
(2-пиридинил)етилиден]карботио-дихидразид, b-TCH2ap, су подложни тион/тиол
таутомеризацији што доприноси смањењу BDE и тиме олакшава пренос атома водоника
у DPPH∙ тесту. Експериментални и теоријски резултати потврдили су да тион/тиол
равнотежа, код m-TCH2ap и b-TCH2ap, додавањем воде помера равнотежу ка тиолном
облику. Ови подаци су добијени из израчунавања ZPE-кориговане енергије, енталпије,
BDE и степена делокализације спина радикала одговарајућих таутомера. Резултати
показују да повећан удео тиолне групе у великој мери доприноси повећању активности
једињења m-TCH2ap и b-TCH2ap. Густина спина радикала у тиолном облику једињења
m-TCH2ap и b-TCH2ap делокализована је скоро преко целе структуре, што није случај
код тион облика. Ова чињеница објашњава значајно повећање антиоксидативне
активности, нпр. IC50 за b-TCH2ap је 0,67 у ДМСО и 0,13 у ДМСО:H2O = 4:1 (у mM).
Други део дисертације је укључивао синтезу дванаест амида циметне киселине
укључујући TCH фармакофоре, синтетисаних купловањем хлорида киселина: циметне,
3-хлорциметне и 4-хлорциметне киселине, као и m-TCH који садрже: пиридин-2-ил,
салицил, 8-хидроксихинолин-2-ил и 2-ацетил групе. Синтетисаним једињењима је
испитиван спектар биолошких активности укључујући антиканцерску и
антимикобактеријску активност. Аналогна синтеза је примењена са 3-
хидроксициметном киселином коришћењем истог сета m-TCH и HATU средства за
купловање. На исти начин су синтетисани амиди кафеинске и ферулинске киселине са
m-TCH који садрже пиридин-2-ил и салицил делове који су коришћени за одређивање
антиоксидативнoг потенцијала. У оквиру процене способности једињења да индукују
смрт малигних ћелија, пет хуманих ћелијских линија је третирано током 24 сата:
колоректални аденокарцином (LoVo), аденокарцином јајника (SkOV-3), аденокарцином
плућа (А549), аденокарцином дојке (MCF-7) и аденокарцином панкреаса (AsPC-1).
Добијени резултати су показали да су ћелије А549 биле најосетљивије на тестирана
једињења док су једињења 3-ClCimTCHsal и 4-ClCimTCH8OH2qu показала супериорну
iv
активност и изабрана су за даља истраживања антиканцерске активности. Иако је 4-
ClCimTCH8OH2qu деловао као снажнији индуктор апоптозне смрти од 3-ClCimTCHsal,
оба једињења у А549 ћелијама су стимулисала заустављање ћелијског циклуса у G0/G1
фази, као и активацију интринзичне каспазне каскаде. Значајна разлика у механизмима
њихове про-апоптозне активности односи се на способност 4-ClCimTCH8OH2qu да
снажно побуди стварање супероксидног анјона у митохондријама, што није детектовано
у ћелијама А549 подвргнутим 3-ClCimTCHsal. Процена њихових антимиграционих
својстава показала је да једињење 3-ClCimTCHsal значајно инхибира покретљивост
А549 ћелија, што није забележено у узорцима третираним са 4-ClCimTCH8OH2qu. Висок
проценат ћелијске смрти које је изазвало једињење 4-ClCimTCH8OH2qu у ћелијама
HaCaT (хумани кератиноцити) и HepG-2 (хумани хепатоцити), коришћених као модели
за процену могућих нежељених дејстава, указало је да ово једињење има неповољан
токсиколошки профил. Напротив, 3-ClCimTCHsal је имао само умерен утицај на
виталност HaCaT ћелија и стога се показао погодним за будућа истраживања његових
антиканцерских својстава.
Капацитет једињења да омета пролиферацију Mycobacterium tuberculosis (Mtb),
патогена одговорног за развој туберкулозе (ТБ), процењен је на три соја из клиничких
изолата, од којих сваки садржи специфичан генотип отпорности на лекове који се
користе у првој линији анти-ТБ терапије: Mtb-InhRif-S без специфичних мутација
повезаних са резистенцијом на изониазид (INH) и/или рифампицин (RIF), Mtb-Inh-R који
има специфичну мутацију за отпорност на INH, и Mtb-Rif-R који има специфичну
мутацију повезану са отпорношћу на RIF. После шест дана инкубације са испитиваним
лековима и INH и RIF као позитивним контролама, CimTCH8OH2qu је био једини који је
успешно смањио раст и размножавање Mtb за више од 90% у сва три третирана соја.
Штавише, једињење CimTCH8OH2qu није изазвало смрт HepG-2 ћелија, што указује на
његов повољан профил хепатотоксичности за разлику од тренутно доступних
терапијских опција за лечење ТБ.
Трећи део ове студије обухватао је испитивање антибактеријске активности четири
серије амида: циметне, 4-хлороциметне и 4-метокси циметне киселине које у амидном
делу садрже: пиридин-2-ил, салицил, 8-хидрокси хинолин-2-ил и 2-ацетил групу.
Антибактеријска студија изведена је на Enterococcus cloacae ATCC13047, Staphylococcus
aureus NCTC 6571, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC
19606, Pseudomonas aeruginosa NCTC 10662, and Escherichia coli ATCC 1175, применом
методе разблаживања. Поједини амиди циметне киселине су показали добру in vitro
активност према свим испитиваним сојевима, односно амиди циметне, 4-хлорциметне и
4-метоксициметне киселине са 2-ацетилпиридинил групом, тј. CimTCH2ap, 4-
MeOCimTCH2ap и 4-ClCimTCH2ap. Штавише, сва једињења су показала значајну
активност у односу на A. baumannii, широко распрострањени опортунистички
интрахоспитални патоген. Најактивнији дериват био је 4-MeOCimTCH2fp, чија је
минимална инхибиторна концентрација способна да инхибира раст и размножавање за
50 % (МИК50) износила 10,4 μmol. Поред тога, да би се успоставила веза између
структуре и антибактеријске активности против A. baumannii, развијен је 3D QSAR
модел (an alignment-independent 3D QSAR model) за идентификацију битних
фармакофорa. У циљу рационализације антимикробног механизма, способност хелације
(координације) гвожђа синтетисаних једињења је одређена UV-Vis
спектрофотометријском методом. Због присуства јаких донорских места, синтетисана
једињења су показала високу способност хелације гвожђа стварањем комплекса са
константом стабилности у опсегу од 107 до 109. Вредности константи стабилности
указује да је интеракција гвожђа са овим једињењима важан корак у метаболитичком
v
путу што је потврђено тиме што је антибактеријска активност према A. Baumannii у
корелацији са променом вредности константе стабилности.
Authors Key words
Thiocarbohydrazide; Cinnamic acid amides; E/Z isomerism; Tautomerism; Antioxidant
Activity; Antibacterial activity; Mycobacterium tuberculosis; Anticancer; Hepatotoxicity;
Acinetobacter baumannii; 3D QSAR
Authors Key words
Тиокарбохидразиди; Амиди циметне киселине; E/Z изомеризација;
Таутомеризациjа; Антиоксидатвна активност; Антибактеријска активност;
Mycobacterium tuberculosis; Антиканцер; Хепатоксичност; Acinetobacter baumannii; 3D
QSAR
Classification
547.496/.497:615.281(043.3)
Type
Tekst
Abstract (en)
Two series of compounds were synthesized in this PhD thesis: Salicylaldehyde (sal) and 2-
Acetylpyridine (2ap) mono- and bis-(thiocarbohydrazones), m-TCH and b-TCH, respectively (first
series), and cinnamic acids amides (second series), in overall twenty eigth compounds.
All synthesized compounds are characterized using both experimental and theoretical methods.
Experimental techniques include FT-IR, NMR and UV-Vis spectroscopy, as well as elemental
analysis used for structural and purity characterization. The use of UV-Vis and NMR spectroscopy,
and theoretical (“quantum chemical”) calculations was applied to get a deeper insight into
experimental data related to the ratio of Z/E isomer and thion/thio tautomerism versus related
antioxidant activity induced by water addition to dimethyl sulfoxide (DMSO) TCHs solution. Water-
induced breakage of intra-molecular hydrogen bond in mono- and bis(salicylaldehyde)TCH, i.e. [(2-
hydroxyphenyl)methylene]carbonothioichydrazide, m-TCHsal, and 2,2'-bis[(2-
hydroxyphenyl)methylene]carbonothioic dihydrazide, b-TCHsal, lead to E to Z isomerization. Good
accordance of experimental data, from 1H and 13C NMR and 2D NOESY spectra, and theoretical
ones, obtained using GIAO/B3LYP-6-311G++(d,p), with respect to geometrical E:Z isomer ratio, e.g.
81:19 for m-TCHsal was obtained. Destabilization of the ground state lowers bond dissociation
enthalpy (BDE) for 11 kcal/mol, and as consequence leads to more extensive electron spin
delocalization in Z-isomers.
Additionally, 2-acetylpyridine based TCH, i.e. E-[1-(2-pyridinyl)ethylidene]-carbonothioic
dihydrazide, m-TCH2ap, and 2,2'-bis[1-(2-pyridinyl)ethylidene]carbonothioic dihydrazide, b-
TCH2ap, are susceptible to thione/thiol tautomerism as a phenomenon which contributes to lower
BDE and effectiveness of the hydrogen transfer to DPPH∙ is facilitated in that manner. Analogously,
experimental and theoretical results confirmed the shift of m-TCH2ap and b-TCH2ap to thiol form by
water addition. These data were observed from the calculation of ZPE-corrected energy, enthalpy,
BDEs, and the extent of radical spin delocalization of the isomers of studied compounds. Results
indicate that increased participation of the thiol group in thiol/thion equilibria highly contributes to
increased radical scavenging activity of compounds m-TCH2ap and b-TCH2ap. The spin density
delocalization in thiol form of m-TCH2ap and b-TCH2ap occupy almost entire structure. Opposite is
true for thione radicals. This fact is observed by a significant increase of antioxidant activity of all
compounds, e.g. 0.67 for b-TCH2ap in DMSO and 0.13 in DMSO:H2O = 4:1 (IC50 in mM).
A second part includes the synthesis of twenty four cinnamic acid amides (cinnamamides) with
TCHs pharmacophore, synthesized by coupling of acid chlorides: cinnamic, 3-chlorocinnamic, 4-
chlorocinnamic and 4-methoxycinnamic acid with m-TCH containing: pyridine-2-yl, salicyl, 8-
hydroxyquinoline-2-yl and 2-acetyl moiety. Synthesized compounds have been investigated for their
biological properties in terms of anticancer and antimycobacterial activity. Analogous synthesis was
applied with 3-hydroxycinnamic acid using the same set of m-TCH and HATU coupling agent.
Finally, amides based on Caffeic and Ferulic acids with m-TCH containing pyridine-2-yl and salicyl
moieties were synthesized in the same manner, and used for study of their antioxidative potential.
Within assessment of compounds’ ability to induce death of malignant cells, five human cell lines
were treated over 24 h: colorectal adenocarcinoma (LoVo), ovarian adenocarcinoma (SkOV-3), lung
adenocarcinoma (A549), breast adenocarcinoma (MCF-7) and pancreatic adenocarcinoma (AsPC-1).
Obtained results showed that A549 cells were the most sensitive to tested treatments, whereas
compounds 3-ClCimTCHsal and 4-ClCimTCH8OH2qu revealed superior activity and were set as the
focus of a further anticancer investigation. Although 4-ClCimTCH8OH2qu acted as a more powerful
inducer of apoptotic death than 3-ClCimTCHsal, both compounds in A549 cells stimulated cell cycle
arrest at the G0/G1 phase, as well as activation of the intrinsic caspase cascade. A notable difference
ii
in mechanisms of their pro-apoptotic activity refers to the ability of 4-ClCimTCH8OH2qu to strongly
arouse generation of superoxide anion in mitochondria, which was not seen in A549 cells subjected
to 3-ClCimTCHsal. Evaluation of their antimigratory properties demonstrated that compound 3-
ClCimTCHsal significantly inhibited mobility of A549 cells, which was not recorded in samples
treated with 4-ClCimTCH8OH2qu. Finally, powerful cytotoxicity of 4-ClCimTCH8OH2qu on HaCat
(human keratinocytes) and HepG-2 (hepatocellular adenocarcinoma) cells that were employed as
models for skin and liver toxicity, uncovered that this compound has disadvantageous toxicity profile.
On the contrary, 3-ClCimTCHsal had only a moderate impact on the vitality of HaCaT cells, and
therefore proved as suitable for future investigations of its anticancer properties. The capacity of
compounds to interfere with proliferation and survival of Mycobacterium tuberculosis (Mtb), which
is a pathogen responsible for the development of tuberculosis (TB), was assessed on three strains
from clinical isolates, each comprising a specific resistance genotype: Mtb-InhRif-S with no specific
mutations associated with resistance to isoniazid (INH) and/or rifampicin (RIF), Mtb-Inh-R harboring
specific mutation for resistance to RIF, and Mtb-Rif-R holding specific mutation associated with
resistance to INH. After 6 days of incubation with investigated drugs, with INH and RIF as positive
controls, CimTCH8OH2qu was the only one that successfully reduced Mtb viability for more than 90
% in all three treated strains. Moreover, compound CimTCH8OH2qu did not induce the death of HepG-
2 cells, which indicates its favorable hepatotoxicity profile compared to current therapeutic options
for the treatment of TB.
A third part of the present study included an antimicrobial study of three series of cinnamic acid
amides: cinnamic, 4-chlorocinnamic and 4-methoxy cinnamic acid and m-TCH containing: pyridine-
2-yl, salicyl, 8-hydroxyquinoline-2-yl, and 2-acetyl moiety. The antimicrobial study against
Enterococcus cloacae ATCC13047, Staphylococcus aureus NCTC 6571, Klebsiella pneumoniae
ATCC 13883, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa NCTC 10662, and
Escherichia coli ATCC 1175 was performed. Some of the cinnamic amides showed good in vitro
activity against all strains tested, i.e. amides based on cinnamic, 4-chlorocinnamic and 4-methoxy
cinnamic acid and m-TCH2ap, i.e. CimTCH2ap, 4-MeOCimTCH2ap и 4-ClCimTCH2ap. Moreover,
all compounds showed acceptable to high activities with respect to A. baumannii, a widely spread
opportunistic pathogen in hospitals. The most active derivative was 4-MeOCimTCH2fp, with MIC50
value of 10.4 (μmol). Additionally, in order to establish relation of structure and antibacterial activity
against A. baumanii an alignment-independent 3D QSAR model was developed for the identification
of pharmacophoric hotspots. In order to rationalize antimicrobial mechanism, the iron chelation
capability of synthesized compounds was determined using UV-Vis spectrophotometric method. Due
to the presence of strong donor sites the synthesized compounds showed strong iron chelating ability
by creating complexes with the stability constant in the range from 107 to 109. Determined stability
constants indicate that interaction of iron and synthesized compounds is an important step in the
reaction pathway of antimicrobial activity against A. baumanii.
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