SYNTHESIS, DIAGNOSIS, EVALUATION OF BIOLOGICAL ACTIVITY AND STUDY OF MOLECULAR DOCKING FOR FUROSEMIDE DERIVATIVE AND ITS COORDINATION WITH SOME METALS Текст научной статьи по специальности «Химические науки»

312 CHEMICAL PROBLEMS 2024 no. 3 (22) ISSN 2221-8688

UDC 541.49:546.561

SYNTHESIS, DIAGNOSIS, EVALUATION OF BIOLOGICAL ACTIVITY AND STUDY OF MOLECULAR DOCKING FOR FUROSEMIDE DERIVATIVE AND ITS COORDINATION WITH SOME METALS

Afraa Sabir Shihab

Department of Chemistry / College of Education for Pure Sciences / Tikrit University

Salahddin, Tikrit, Iraq https://orcid.org/[email protected]. iq

Received 13.01.2024 Accepted 04.03.2024

Abstract: This study includes the preparation and characterization of new compound (4-bromo-5-(N-((4-chlorophenyl) (1,1-dioxide-3-oxobenzo isothiazol-2(3H)-yl)methyl)sulfamoyl)-2-((furan-

2-ylmethyl)amino)benzoic acid) from the reaction of furosemide, Saccharin andp-bromo benzaldehyde in a molar ratio 1:1:1 in ethanol. All the complexes are prepared from the reaction of Mannich bases with metal nitrate salts of transition metals such as Co, Ni, Cu and Zn in equimolar ratio (1:1) in ethanol solvent. The prepared compounds were characterized by elemental analysis (C.H.N.S), H-NMR, FT-IR, molar conductivity and magnetic sensitivity were determined. The results showed that furosemide derivatives bi-dentate are coordinated by nitrogen and oxygen atoms with metal, giving tetrahedral geometry. The antibacterial activity was studied for ligands and their complexes using the agar diffusion method. All the prepared compounds were studied and applied to two types of bacteria at different concentrations. It was showed, that the obtained complexes demonstrate a higher inhibitory effect on Staphylococcus aureas bacteria than on Pseudomonas aeruginosa bacteria.

Keywords: Furosemide, Mannich base, Mannich reaction, para bromobenzaldehyde, Saccharin. DOI: 10.32737/2221-8688-2024-3-312-323

1. Introduction

The Mannich bases were obtained by aldehyde condensation with a combination containing active hydrogen (acidic) and a primary or secondary amine or sometimes ammonia via a Mannich reaction [1-4]. The Mannich bases apply to a comprehensive and essential life. Especially those compounds that contain heterogeneous rings in their composition have been used as antibacterial agents [5]. In addition, a huge number of Mannich bases have been obtained [6], which have proven their ability as an antidote to various diseases and are considered essential substances in the preparation of various active molecules. The Mannich bases have one lone pair of electrons on the nitrogen atom that can donate it to another atom forming good

important complexes used for medicinal efficacy against fungi and bacteria [7-8].

The Mannich bases has a one lone pair of electrons on the nitrogen atom can donate it to another atom forming a good important complexes used as medicinal efficacy against fungi and bacteria [7-9]. Chelating compounds for Mannich bases that contain active carbonyl and amine groups, can coordinate with transition metals to form different geometric structures, such as an octahedral hexahedral coordinate, a tetrahedral shape, or a tetrahedral and square planar coordinate. Due to these properties, numerous researchers have investigated Mannich complexes and examined their pharmacological properties [9-11].

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2. Experemental part

2.1. Materials Employed: All chemicals utilized were procured from Fluka and Aldrich Companies.

2.2. Used Instruments

Infrared spectra of the synthesized compounds were recorded using an FTIR-8400S instrument provided by SHIMADZU. The spectra were recorded in the range of 4000-400 cm-1 using KBr pellets. (1H, NMR) Nuclear Magnetic Resonance spectra were acquired using a Bruker Spectrometer (500 MHz), respectively, in the d6-DMSO solvent. The measurements were conducted using an SMP10 Automatic Melting Point apparatus from the British company STUART. The Magnetic susceptibility measurements of certain solid metal complexes were carried out at the laboratory temperature using a Sherwood Scientific instrument. The Faraday method was employed for these measurements.

2.3. Preparation Methods Synthesis of Mannich Base Aj.

Mix 3.307 g of furosemide with 2.05 g of sodium saccharin in absolute ethanol in a water bath and then add 1.85 g of 4-bromobenzaldehyde in absolute ethanol drop by drop to the reaction mixture for one hour with continuous stirring for two hours. The mixture color changed from colorless to yellow. The sediment was recrystallized using absolute ethanol after the excess solvent had evaporated. A yellow precipitate was produced with a melting point between 186 and 188° Celsius, and 92 % yield.

Synthesis of Mannich Bases Complexes A2-A5 To obtain A2 complex, 2.26 g of base A1 dissolved in 5 ml of pure ethanol was added to 0.01 mol of metal nitrate salt dissolved in 3 ml of absolute ethanol, stirred for 3 hours, then raised for two hours and left to dry. As a result, the residue was recrystallized from pure ethanol. All other complexes were obtained by similar methods. Table 1 shows the physical properties of the prepared complexes A2-A5.

Table 1. Physical properties of t he comp exes A2-A5

No Complexes Colour M. p., (oC) Yield, % Cond.Am fi-1 cm2 mol-1 Meff (BM)

A2 [Co(Ax) (NO3)2] Red 230-232 90 8.4 3.47

A3 [Ni(Ax) (NO3)2] Light green 262-264 85 6.2 2.89

A4 [Cu(A1)(NO3)2] Dark brown 266-268 83 3.2 1.63

A5 [Zn(A1)(NO3)2] Brown red 245-247 92 5.6 2.83

The Biological Activity Study

The biological activity study for the Mannich bases and its complexes are taken against two types of bacteria (Staphylococcus Aureus) and (Pseudomonas aeruginosa), using a nutrient medium. The solutions of Mannich base and their complexes were prepared using a DMSO solvent with different concentrations

(25, 50, and 100 mg/ml). In this study, we use the agar-well diffusion method and its effect on inhibiting bacteria growth by measuring the diameter of 6 mm circulated on the agricultural medium surface. After this, the dishes were incubated at 37° C for 24 hours. The effectiveness of all compounds was calculated by measuring the inhibition zone diameter.

3. Results and discussion

The compound A1 (4-bromo-5-(N-((4- sulfamoyl)-2-((furan-2-ylmethyl) amino

chlorophenyl) (1,1-dioxido-3- (benzoic acid) was prepared from the reaction of

oxobenzo[d]isothiazol- 2(3H)-yl) methyl) SodiumSaccharin with 4-bromobenzaldehyde

and furosemide in ethanol as in the following mechanisms below:

Ar"

—C-

-H +H,N—Ar1

I

Ar"—С

Л

ft-H-ei. I

Ar"

ОН

I

Ar"—С-N—H

I I

H Ar"

EtOH

H.

Ar"—C-Qi—H

-H20

i i

H

Ar1

Ar"

I ^H Ar"NH2= Furosemide

ArN—C-N^ Ar'NH2 =4- bromobenzaldehyde

i Ar' ArNNa= Sodiumsaccharin

H

Scheme 1. Reaction mechanism scheme 3.1. Infrared Spectra (FT-IR)

Scheme 2. The prepared compounds A1-A5 The spectral peaks for the compound Ai (Fig.1) at the frequency 3425 cm-1 belonging to

the group of O-H, as well as the appearance of an intense peak at the frequency 3350 cm-1 attributed to the group of N-H, and also the formation of a peak at the frequency 3120 cm-1 belonging to the group of C-H aromatic, the absence of the double shift belonging to the group of NH2, which means that the interaction occurred through the group NH2 as well as the appearance of a peak at a frequency of 1705 cm" 1 attributed to Frequency C = O. The appearance

The appearance of the M-N group absorption beam in the spectra of the complexes and its absence in the ranges of the Mannich bases is a clear indication of the consistency

of two peaks belonging to the group SO2, one of which appears at the site 1321 cm-1 and the other appears at the site 1163 cm- 1. The appearance of an intense peak at the frequency 1672 cm-1 is attributed to the group of C = C of the aromatic ring, as well as the appearance of a peak at the frequency 1442 cm-1 belonging to the group of (CH2), and the formation of a peak at the frequency 752 cm-1 belonging to the group of C- Br as shown in Fig. 1.

between the metal and the nitrogen atom of the amine group that appeared in the region 516478 cm-1 [12]. Table 2 shows infrared spectrum peacks (cm-1) for prepared complexes A2-A5.

Table 2. FT-IR Spectrum

)eacks for the prepared complexes A2-A5 (cm-1

No Complexes O-H N-H C=O SO2 M-N M-O C-Cl

Sym. Asym.

a2 [Co(Ai)2(NO3)2] 3398 3341 3313 1722 1336 1176 516 881 754

A3 [Ni(Ai) (N03)2] 3402 3373 3348 1724 1338 1178 453 663 754

A4 [Cu(Ai)(N03)2] 3400 3325 3284 1724 1336 1178 455 831 752

A5 [Zn(Ai)(N03)2] 3426 3348 3254 1672 1338 1168 478 887 752

m — V V I Mil ijyr TTt~ ! " " • } ! J~ ! j I fll ill! I

A A! 1 \\ j u I

• n V • >|f " il! lutfW i ; - . " if

It ft ! 1 ii. ; 1..... 111 fl ¡'i ' i ..... . IU i i ll M.l ä

1 1 1 /^v' ? O ?

I ,1 SWoC" In • O-^Vd y ji! ! 1 ... i—ui.......; ..i .t 1 -Uli' UL4- ;—

« .......... 1..,. 1. . . . 1 . . . . 1 . > ■ ■ i • H •

Fig. 1. Infrared Spectrum of the A1 compound

FT-IR spectrum of the (A3) compound 3402 cm-1 attributed to O-H group; at 3373 and (Fig. 2) shows following absorbance peaks: at 3348 cm-1 for N-H group; at 1724 cm-1 for the

C=O group; at 1338 and 1178 cm-1 for the SO2. 663 cm-1 and 453 cm-1 reflex the Ni-O and Ni-N For the nickel complex the absorbance peaks at bonds, respectively.

100 — %T ; oo-f 80-j 7060 -50 — 40 — 30 — 20 ~ 10 ~ 0 — 10 — 40 I I Y r "°w MM 0 r—i ! j 1 1 )— S- fl 61 i 1 II I h 1 1 ° 1 1 a I In Î3Z& PtRH "M 11 Uli 11 J Ii J f I \ fli j I s $ il n 1 l i g X r>* IIP ü CS äs l 1 2 1 l 5»

00 3600 3?00 2B00 2400 20 00 1800 1(500 1400 1200 1000 800 600 4

Fig. 2. FT-IR spectrum of the compound A3

3.2. Nuclear Magnetic Resonance Spectrum (H-NMR)

The proton N.M.R. spectra of the compounds

were measured to support the expected structure of the compound using a solvent DMSO-d6.

Fig. 3. 1H-NMR spectrum of the compound A1

The N.M.R. spectrum of 1H-NMR of this compound showed a singlet signal at 4.6 ppm belonging to the (CH2) group associated with the five-ring of the furosemide, a sign at 6.01 ppm belonging to the CH that connects to the three starting compounds, two signals at the range 6.376.43 ppm belonging to (3H) for the furan ring, a sign at the content 7.3-7.9 ppm belonging to the protons of the aromatic rings of the prepared compound, and a signal at 8.26-

3.4 Biological Activity

Table 4 and Figures 4 and 5 show the effect of Mannich bases and their prepared complexes on bacteria, and it was found that the prepared compounds have varying strength effectiveness in inhibiting of the growth of studied bacteria. It was also noted that the inhibitory ability of metal complexes was higher than that of Mannich bases in the development of selected bacteria due to the small invasion shown by bacteria to such metals. It was also noted that the inhibition of the growth of the

8.66 ppm belonging to the two (N-H) groups of f furosemide. Finally, a sign appears at 13.41 ppm belonging to the OH terminal group of furosemide as shown in Fig. 3. 3.3 (C.H.N.S) Analysis of elements.

Careful elemental analysis of the prepared compound's was stduded to prove the validity and calculate the practical percentage compared with theoretical percentage for the compounds. All the data were shown in Table 3.

bacteria type Staphylococcus aureus is higher than the inhibition of the development of the bacteria type Pseudomonas aeruginosa, and this is due to the structure of the cell wall as the bacteria positive for the dye Cram contain less amino acids than the harmful bacteria for dye Cram. The negative bacteria of the dye gram contain fatty substances higher than the positive gram. The highest inhibition of bacteria was for complex A3 [13], and the lowest inhibition was for the compound A5.

Comp. No. Streptococcus mutants Pseudomonas aeruginosa

Conc. (mg/ml) 25 50 100 25 50 100

Ai 14 19 23 11 14 18

a2 19 23 25 12 18 20

A3 20 22 26 14 17 22

Table 3. Elemental analysis of the compounds Ai-A5

Comp. No. Formula Calculated / Theoretical

% C % H % N % S

Ai C26H19N3O8S2BrCl 45.81 / 45.86 2.82 / 2.81 6.14 / 6.17 9.44 / 9.42

A2 [Co(A1) (N03)2] 36.17 / 36.15 2.23 / 2.22 8.18 / 8.11 7.43 / 7.42

A3 [Ni(A1) (N03)2] 36.17 / 36.16 2.25 / 2.22 8.15 / 8.11 7.44 / 7.42

A4 [Cu(A1)(N03)2] 35.94 / 35.96 2.24 / 2.21 8.04 / 8.06 7.35 / 7.38

A5 [Zn(A1)(N03)2] 35.86 / 35.88 2.18 / 2.20 8.01 / 8.05 7.34 / 7.37

Table 4. Inhibition radius (mm) of Mannich bases and their prepared complexes against the studied

bacteria

A4 21 24 31 19 22 29

a5 9 14 19 7 11 16

Ampicillin 23 26 32 21 26 32

Amoxicillin 21 24 34 20 25 31

The inhibitory activity of (in a) picul nets agniucsl Streptococcus mutants

40 30

20 10 0

25 mg/ml 50 mg/ml ■ 100 mg/ml

Fig. 4. Biological activity of the Streptococcus Mutants.

Ihr lahibMton miMI) nf Hml prmlutt* •xslnrtl l'tmdf>miifia\ ttrrugmn

40 30

20 10

0

25 mg/ml 50 mg/ml ■ 100 mg/ml

Fig. 5. Biological activity of Pseudomonas Aerugnosa

3.5 Study of Molecular Docking Compounds [14, 15]

Molecular docking of some prepared compounds Ai, A3, A4 was carried out on one line of the bacterium Pseudomonas aeruginosa, where the process of energy recovery of the studied carriers was completed in order to obtain the most stable vacuum form (lowest interfering energy). The composition of Pseudomonas aeruginosa bacteria was

downloaded from the World Bank Protein Bank (6R3X receptor) and a personal calculator was used. In this case, the binding energies of the compounds were calculated as indicated in Table 5. The study of molecular fusion of the obtained organic derivatives made it possible to determine the number and types of bonds through which these obtained derivatives bind to amino acid residues found in the active center through the formation of a series of bonds [16].

Table 5. Values of binding energy, hydrogen bond lengths and amino acid effect between prepared _compounds and receptor (6R3X) One line of Pseudomonas aeruginosa_

Comp. No Correlation Energy Docking Score RMDS Hydrogen bond Other amino acids affected by Vandervaalz and other forces Number of amino acids affected

Number of ydrogen bond Associated amino acidosis Hydrogen bond length

Ai -6.286 2.27 3 Arg.517 Met. 553 Arg.68 2.41(A) 1.92(a) 2.04(a) Val.555, Arg.438 Asp.253, Leu.260 Pro.556,Asn.69 Glu.258,Thr.256 Asn.554 9

A3 -7.389 2.38 3 Tyr.223 Arg.331 Arg489 1.82(A) 2.08(a) 2.40(a) Ser.249,Arg.335 Asp.332,Leu.221 Glu.255,Met.436 Gly.534,Thr.487 Ala.220,Lys.297 Ser.249,Asn(351,348) Ter(407,523,498,238) 18

a4 -6.631 4.19 3 Arg.489 Arg.335 Arg.331 2.28(A) 2.04(a) 2.00(a) Val.333,Glu.500 Asn.(501,351) Thr.487,Ala.485 Asp.332,Phe.533 Ser.294,Ter.(532,409, 407,503,487,) 14

The study showed that compound Ai reacts with amino acid residues located in the active center, forming two types of bonds. First, three hydrogen bonds are formed, the first of which connects the amino acid residue Arg.68, located in the active center, with the electron pair of the oxygen atom of the pentaring sulfoxide group, and the second and third connect the amino acid residues Met.553, Arg.517, located in the active center , with the electron pair of the oxygen atom of the hydroxyl group of the carboxylic acid. Furthermore, a number of amino acids are exposed to Van der Waals forces, as shown in Table 5.

It has been discovered that compound A3 interacts with the amino acid residues found in the active site by forming two types of bonds, specifically three hydrogen bonds. The first hydrogen bond linking the amino acid residue Arg.331, Arg.489 located in the active site with the electron pair of the penta-ring sulfoxide oxygen atom, and the third linking the amino acid residue Tyr.409 located in the active site

with the electron pair. For an oxygen atom of the sulfamide group, a Pi- Alkyl type bond residue of the amino acid Arg.331 which resides in active situ with the electron pairs of the aromatic ring, and a number of amino acids affected by Van der Waals forces (see Table 5).

The study showed that the compound (A4) reacts with the amino acid residues that reside in the active site by forming three hydrogen bonds. One of them linking the amino acid residue Arg.489 located in the active site with the electron pair of the penta-ring sulfoxide oxygen atom, and the second one bonding the amino acid residues Arg.335 located in the active site with the electronic pair of the sulfamide group oxygen atom, and the third one linking the amino acid residues. Arg.331 is in active location with the electron pair of an oxygen atom of the hydroxylic acid carboxylic group. A Pi-Alkyl type bond the residue of the amino acid Val.333 which resides in active situ with the electron pairs of the furan aromatic ring, and a number of amino acids affected by Van der

Waals forces as in Table 5 above.

Fig. 6. Interactions Ai with amino acids in 3D and 2D

Fig. 7. Interactions A3 with amino acids in 3D and 2D

Figures 6, 7, and 8 show two-dimensional and three-dimensional representations of molecular anchoring and

association between prepared compounds and the 6R3X receptor (6R3X) single line of Pseudomonas aeruginosa bacteria.

Fig. 8. Interactions A4 with amino acids in 3D and 2D

4. Conclusions

Mannich base Ai was obtained from the reaction of furosemide, sodium saccharin, and bromobenzaldehyde. Then we obtained the complexes based on the Mannich base for the ions of the elements Co(II), Ni(II), Cu(II) and Zn(II). The symmetry of the Mannich base with the metals in the complexes A2-A5 was through the nitrogen atom of the amine group and the

oxygen atom of the furosemide group and was used. These complexes are tetrahedral in shape.

The results of the biological study showed that Mannich base and its complexes have a higher inhibitory activity against Staphylococcus aureas bacteria than against Pseudomonas aeruginosa bacteria.

References

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FUROSEMID TÖROMOSiNiN SiNTEZi, DiAQNOSTiKASI, BiOLOJi AKTiVLiYiNiN QiYMOTLONDiRiLMOSi, MOLEKULYAR DOKÎNQi VO BOZi METALLAR iLO

KOORDiNASiYASININ ÖYRONiLMOSi

Afraa Sabir $ihab

Kimya Bölmdsi / Tdbidt Elmhri ûçûn Tdhsil Kolleci / Tikrit Universiteti Sdlahdddin, Tikrit, iraq

[email protected]. iq

Xülasa: Bu tadqiqat yeni (4-bromo-5-(N-((4-xlorofenil) (1,1-dioksid-3-oksobenzo izotiyazol-2(3H)-il)metil)sulfamoil)2-((furan-2-ilmetil)amino)benzoy tur§usu) birla§masinin furosemid, saxarin va p-brom benzaldehidin 1:1:1 mol nisbatinda etanolda reaksiyasindan alinmasina va xassalarinin öyranilmasina hasr olunmu§dur. Bütün komplekslar Co, Ni, Cu va Zn ke9id metallarinin nitrat duzlari ila Mannix asaslarinin ekvimolyar nisbatda (1:1) etanolda reaksiyasindan sintez edilmi§dir. Sintez edilmi§ birla§malar element analizi (CHNS), 1H-NMR, iQ-spektroskopiya metodlari ila xarakteriza edilmi§, onlarin molyar ke?iricilik va maqnit hassasligi tayin edilmi§dir. Naticalar göstarir ki, furosemid töramalari azot, oksigen atomlari, metal ila bi-dentant koordinasiya edir va naticada tetraedrik qurulu§ amala gatirir. Liqandlarin va onlarin komplekslarinin antibakterial aktivliyi aqar-diffuziya üsulu ila öyranilmi§dir. Alinmi§ birla§malar müxtalif qatiliqlarda iki növ bakteriyaya qar§i tadqiq va tatbiq edilmi§dir. Müayyan edilmi§dir ki, alinmi§ komplekslar Pseudomonas aeruginosa bakteriyalarina nisbatan Staphylococcus aureas bakteriyalarina qar§i daha yüksak inhibitor tasiri göstarirlar.

A?ar sözlar: furosemid, Mannix asaslari, Mannix reaksiyasi, parabromobenzaldehid, saxarin.

СИНТЕЗ, ДИАГНОСТИКА, ОЦЕНКА БИОЛОГИЧЕСКОЙ АКТИВНОСТИ И ИЗУЧЕНИЕ МОЛЕКУЛЯРНОГО ДОКИНГА ПРОИЗВОДНОГО ФУРОСЕМИДА И ЕГО КООРДИНАЦИИ С НЕКОТОРЫМИ МЕТАЛЛАМИ

Афраа Сабир Шихаб

Факультет химии /Педагогический колледж эстественных наук / Университет Тикрит

Салахдин, Тикрит, Ирак [email protected], https://orcid.org/0000-0003-1006-5919

Абстракт: Настоящее исследование посвящено получению и изучению свойств нового соединения (4-бром-5-(№°((4-хлорфенилХ1,1-диоксид-3-оксобензоизотиазол-2(3Н)-

ил)метил)сульфамоил)- 2-((фуран-2-илметил)амино)бензойная кислота) реакцией фуросемида, сахарина и p-бромбензальдегида в мольном соотношении 1:1:1 в этаноле. Все комплексы получены реакцией оснований Манниха с нитратными солями переходных металлов, таких как Co, Ni, Cu и Zn, в эквимолярном соотношении (1:1) в растворителе этаноле. Полученные соединения были охарактеризованы элементным анализом (CHNS), *Н- ЯМР, ИК-спектроскопией, а также определением молярной проводимости и магнитной чувствительности. Результаты показали, что производные фуросемида бидентатно координируются атомами азота и кислорода с металлом, придавая тетраэдрическую геометрию. Антибактериальную активность лигандов и их комплексов изучали методом агар-диффузии. Все полученные соединения были изучены и применены к двум видам бактерий в разных концентрациях. Показано, что полученные комплексы проявляют более высокий ингибирующий эффект по отношению к бактериям Staphylococcus aureas, чем к бактериям Pseudomonas aeruginosa.

Ключевые слова: фуросемид, основание Манниха, реакция Манниха,

парабромбензальдегид, сахарин.