Synthesis and Characterization of Some Transition Complexes with 4- [2-(2-chlorobenzylidene)hydrazinyl]-7H-pyrrolo[2, 3-d]pyrimidine: Antimicrobial and Cytotoxic Activity

doi:10.21203/rs.3.rs-2578421/v1

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Synthesis and Characterization of Some Transition Complexes with 4- [2-(2-chlorobenzylidene)hydrazinyl]-7H-pyrrolo[2, 3-d]pyrimidine: Antimicrobial and Cytotoxic Activity

https://doi.org/10.21203/rs.3.rs-2578421/v1

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Ten new transition metal complexes (1–10) with 4-[2-(2-chlorobenzy-lidene)hydrazinyl]-7H-pyrrolo[2,3-d]pyrimidine (HPPHoCB) was prepared. 4-[2-(2-Chlorobenzylidene)hydrazinyl]-7H-pyrrolo[2,3-d]pyrimidine of general formula [C₁₃H₁₀ClN₅], was prepared through the condensation reaction of 2-chlorobenzaldehyde with pyrrolopyrimidinehydrazide. The characterization of the new formed compounds was done by physico-chemical studies, conductance measurement, magnetic susceptibility data, ¹H-NMR, UV-Visible, ESR, FT(IR) spectroscopy and elemental analysis. In addition, the structure of the complexes Cr(III), Fe(II), Co(II), Ni(II) and Cu(II) has been determined by X-ray diffraction method. The prepared HPPHoCB ligand act as bidentate ligand and coordinate with central metal ions through nitrogen of azomethine and pyrrolo groups. The low molar conductance values in nitrobenzene indicate that the metal complexes are non-electrolytes in nature. The magnetic moments and electronic spectral data suggest octahedral geometry for the Cr(III), Mn(II), Co(II), Ni(II), and Fe(II) complexes, tetrahedral geometry for Zn(II), Cd(II), Hg(II) complexes and square planar for Pd(II) and Cu(II) complexes. The HPPHoCB ligand and its metal complexes were screened for antimicrobial activities against two Gram-positive bacteria (Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121), two Gram-negative bacteria (Escherichia coli MTCC 1652 and Pseudomonas aeruginosa MTCC 741), and Fungus (Aspergillus niger, Aspergillus flavous and Fusarium species) as well as for cytotoxic studies against Artemia salina . The synthesised metal complexes were found more active against both bacterial as well as fungi in antimicrobial and cytotoxic screening test than that of HPPHoCB ligand.

Copper

Nickel

Palladium complexes

Pyrrolopyrimidine

Antimicrobial

Cytotoxic

The design and study of well-arranged metal-containing pyrrolopyrimidine with N – donor atom is an interesting field of inorganic and bioinorganic chemistry [1–11]. In-situ one-pot template condensation reactions lie at the heart of the coordination chemistry. It is generally known that pyrrolic compounds, such as polypyrroles, poly-or heteroarylpyrroles, exhibit electronic delocalization, endowing these molecules with electric conductivity and oxidizability. Other 2-aminopyrrole-3-carbonitrile derivatives with a β-enaminonitrile moiety are likewise well known to be highly reactive and have been employed as intermediates in the production of novel pyrrolo[2,3-d]pyrimidine derivatives [2]. 7-Deazapurine (pyrrolo[2,3-d]pyrimidine) is a heterobicyclic system with structural similarities to purine and indole, and as such, it could be predicted to have pharmacological and possibly therapeutic utility. This heterosystem is common in nature and is found in antibiotics such as tubercidin, toyocamycin, sangivamycin, cadeguomycin, and rigidin alkaloids [3]. Furthermore, several 2,4-diaminopyrrolo[2,3-d]pyrimidine derivatives were discovered to have significantly higher BBB penetration capability and high-lipophilic antioxidant activity with protective effects [4]. Some 2,4-diaminopyrrolo[2,3-d]pyrimidines, for example, and 6,7-dimethyl-2,4-dipyrrolidin-1-yl-7H-pyrrolo[2,3-d]pyrimidines have antioxidant, neuroprotective, and antiasthmatic properties [5]. Furthermore, organofluorine compounds have a wide range of interesting pharmacological and agrochemical properties. A series of fluoro-substituted 4-(dialkylamino)pyrrolo[2,3-d] pyrrolo[2,3-d] pyrrolo[2,3-d] pyrrolo[ pyrrolo[2,3-d] pyrrolo[2,3-d] pyrrolo[ Pyrimidines that bind well to the corticotrophin-releasing hormone type 1 receptor (CRHR1) have been made and reported, and some other compounds have been suggested as good candidates for making non-peptide PET radioligands with 18F for CRHR [11].

Keeping in view of medicinal and industrial applications of pyrrolopyrimidine and potential chemistry of transition metals; the work aimed at synthesis of transition metal complexes of novel Schiff base of 4-[2-(2-Chlorobenzylidene) hydrazinyl]-7H-pyrrolo[2,3-d]pyrimidine [HPPHoCB]. The synthesized HPPHoCB ligand and its transition metal complexes was characterized by different techniques like physico-chemical studies, elemental analyses, spectral studies (UV-Vis, FT(IR), PMR, ESR), X-ray powder diffraction studies, and magnetic and conductance measurements. The biopotency of HPPHoCB ligand and its transition metal complexes as antimicrobial and cytotoxic agents were investigated. The ligand and its transition metal complexes are new, reported here by the group for the first time.

Materials And Methods

All commercially available chemicals and reagents were of analytical- or reagent-grade purity and used as received.

Physical Measurements

PMR spectra were recorded at room temperature on a BRUKER AVANCE III HD NMR 500 MHz in DMSO-d₆, using TMS as the internal standard. FT(IR) spectra were recorded on a BRUKER FT-IR spectrophotometer in the 4000–500 cm^− 1 region using KBr pellets. The chemical elemental analysis for the determination of C, H, N and Cl was done the Carlo-Erba LA-118 microdosimeter. Metal ions were determined following the method described by Patil et al [12]. Magnetic susceptibility measurements were carried out on solid complexes using the Gouy’s method [13]. X-ray diffraction analysis of compounds Cr(III), Fe(II), Co(II), Ni(II) and Cu(II) were carried out on a Nonius KappaCCD diffractometer (MoKα radiation, λ = 0.71069 Å) at room temperature. The structures of complexes Cr(III), Fe(II), Co(II), Ni(II) and Cu(II) was solved by the direct method using SHELXS-86 and SIR-97 software and refined by least squares in the anisotropic approximation for nonhydrogen atoms (CRYSTALS). The hydrogen atoms were refined isotopically. In complexes, Fe(III), Co(II), Ni(II) and Cu(II), all hydrogen atoms were included in the refinement in geometrically calculated positions (except for water molecules in which hydrogen atoms were not located). The C–H and N–H bond lengths varied in the 0.93–0.98 and 0.86–0.89 Å ranges, respectively. The thermal factors UH were taken to be 1.2–1.5 times as high as the Ueq values of the carbon and nitrogen atoms. The solutions of 10^− 3 M concentration were prepared in HPLC-grade nitrobenzene, and the experiment was carried out at room temperature. ESR spectra were recorded on X-Band at frequency of 9.1 GHz under the magnetic field 3000 Guass on a varian E-112 ESR spectrometer at SAIF, IIT Bombay.

Synthesis

Synthesis of the HPPHoCB ligand

Pyrrolopyrimidinehydrazide prepared by reported method [14]. A hot solution of 2-chlorobenzaldehyde (0.11 mol) in methanol (25 mL, 50–60°C) was added to a magnetically stirred solution of pyrolopyrimidinehydrazide (0.10 mol), in warm methanol (25mL). The reaction mixture was refluxed for 6–7 h and cool the mixture. The resulting precipitate was filtered, washed with 50% methanol, and dried under vacuum and crystallization from methanol gave HPPHoCB.

Synthesis Of Metal Complexes Of 4-[2-(2-chlorobenzylidene) Hydrazinyl]-7h-pyrrolo[2,3-d]pyrimidine (Hpphocb)

The metal complexes were synthesized by reacting aqueous ethanolic solutions of acetates of CrCl₃ (0.52g, 0.3mmol), FeSO₄ (0.75g, 0.5mmol), CoCl₂.6H₂O (1.19 g, 0.5 mmol), NiCl₂.7H₂O (1.28 g, 0.5 mmol), PdCl₂ (0.89g, 0.5mmol), CuCl₂ (0.85 g, 0.5 mol), ZnSO₄.H₂O (1.45g, 0.5 mmol), CdCl₂ (0.92g, 5mmol), HgCl₂ (1.36g, 0.5mmol) and MnCl₂ (0.63g, 0.5mmol) with the hot methanolic solutions of the HPPHoCB (2.71g, 1.0mmol). The pH of the reaction mixtures was adjusted to 7 with dilute alkali and digested to 7-12h. The solid complexes formed were filtered off and washed several times with hot water, aqueous methanol to remove unreacted metal salts or ligands, and finally with acetone and vacuo dried.

Antimicrobial Assay

Test Microorganisms

Two Gram-positive bacteria (Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121), two Gram-negative bacteria (Escherichia coli MTCC 1652 and Pseudomonas aeruginosa MTCC 741) were used in the present study for evaluation of antimicrobial activity of the synthesized compounds. All the bacterial cultures were procured from Microbial Type Culture Collection (MTCC), IMTECH-Chandigarh. Medium used for the antimicrobial testing was Muller Hilton agar media and autoclaved at 15 lbs/in² for 15 min.

Antibacterial Activity

The antimicrobial activity of the newly synthesized compounds was assayed by using agar wells diffusion technique [15]. For the evaluation of antimicrobial activity, the size of inoculum was adjusted to approximately 108 colony-forming units (cfu/mL) by suspending the culture in sterile distilled water. Petri dishes containing 20mL of Muller Hilton agar medium were swabbed with a culture of the respective microbial strains and kept for 15 min for the absorption of culture. Sterile borer is used to create the wells (6mm in diameter), and we added 100 µL solution of each compound of 4.0mg/mL concentration reconstituted in the DMSO on the preinoculated plates. All the plates were incubated at 37^oC for 24 hrs. antimicrobial activity of all the synthesized compounds was determined by measuring the zone of inhibition around the wells. DMSO was used as a negative control, whereas Streptomycin was used as positive control. This procedure was performed in three replicate plates for each organism.

Determination Of Minimum Inhibitory Concentration (Mic)

MIC of all the compounds was determined by the modified agar well diffusion method [16]. Different concentrations ranging from 10 to 1000 µg/mL of synthesized compounds were made from the stock solution of 4 mg/mL in DMSO. A 100 µL volume of each dilution was introduced into wells (in triplicate) in the agar plates already seeded with 100 µL of standardized inoculum (108 cfu/mL) of the test microbial strain. These plates were incubated at 37^oC for 24 h and observed for the inhibition zones. Streptomycin antibiotic was taken as positive control.

Antifungal Activity

The cup-plate method was used [17, 18] to test the compounds against Aspergillus fumigatus and Aspergillus flavus. A micropipette was used to fill the 5 mm diameter and 1 mm thick discs with the test solution, and the plates were incubated at 37^oC for 72 hours. The test solution diffused during this time and influenced the growth of the inoculated fungi. The diameter of the inhibition was measured after 36 hours of incubation at 37^oC. Minimum inhibitory concentration studies were conducted on compounds that showed promising antifungal activity. The minimum inhibitory concentration (MIC) of an antifungal compound was the lowest concentration that inhibited the visible growth of microorganisms after overnight incubation. In diagnostic laboratories, MIC was used to approve microorganism’s resistance to antimicrobial agents as well as to screen the activity of new antimicrobial agents.

In Vitro Cytotoxicity

The cytotoxicity (brine shrimp bioassay) of the synthesised HPPHoCB ligand and its Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Pd(II), Cu(II), Zn(II), Cd(II), and Hg(II) complexes was tested [19]. Shrimp eggs were placed in one side of a divided tank that contained artificial sea water (38 g NaCl/1000 mL tap water), while the other half of the divided tank was covered. The shrimp were given 48 hours to hatch and develop into nauplii. For a bioassay, the newly hatched shrimp were removed. Different concentrations of dried complexes (2.5, 5, 7.5, 10, and 12.5 mg/10 mL) were added to the sample tubes. In order to test the complexes' cytotoxic potential, DMSO was dissolved in them. 10 live shrimp were placed into each test tube using a Pasteur pipette. To verify the test procedure and the conclusions drawn from the test agent's cytotoxic activity, a control group was included. After 24 hours, the tubes were examined with a magnifying glass, and the number of survived nauplii in each vial was counted, as well as observations for each vial. Each experiment had five replicates and was repeated three times. The LC50, 95% confidence limit, LC90, and chi square values were calculated using the recorded observations. In cases where control deaths occurred, the data were corrected using Abbott's formula [20]: % deaths = [(test-control)/control] x 100.

General Studies

The pyrrolopyrimidinehydrazide was synthesised using a well-established technique described in the literature [14]. The HPPHoCB ligand was synthesised in a single step by direct condensation of pyrrolopyrimidinehydrazide and 2-chlorobenzaldehyde in a molar ratio (1:1) with a quantifiable yield. Scheme-1 illustrates the synthesis of HPPHoCB ligand. The complexes are soluble in most organic solvents but not in water or ethanol. The elemental analysis data shows that the metal to ligand ratio in all complexes is 1:2 (expect Cr (III) complex). The complexes are powdered solids that are coloured and non-hygroscopic. The complexes molar conductance values at room temperature (measured in 10^− 3M nitrobenzene) range from 0.679 to 11.51 ohm^− 1 cm² mol^− 1, indicating that they are non-electrolytes [21]. TLC was used to ensure the purity of the ligand and its metal complexes.

Table-1

Physico-chemical and analytical data of HPPHoCB ligand and its metal complexes

Comp	Color	MW	% Yield	MP/DP	Element Content					Cond	MM
Comp	Color	MW	% Yield	MP/DP	M	C	H	N	Cl	Cond	MM
HPPHoCB	L. brown	271.000	81.36	189	-	57.49	3.71	25.78	13.05	-	-
Cr(PPHoCB)₃	Green	861.996	79.34	261	6.03	54.29	3.13	24.36	12.36	1.173	3.87
Mn(PPHoCB)₂	White	594.938	77.98	228	9.23	52.44	3.03	23.53	11.93	0.778	-
Fe(PPHoCB)₂	Blue	595.845	83.20	238	9.37	52.36	3.02	23.5	11.91	1.054	5.51
Co(PPHoCB)₂	Brown	598.993	79.30	244	9.85	52.09	3.01	23.37	11.90	0.786	4.51
Ni(PPHoCB)₂	Green	598.693	77.98	258	9.8	52.11	3.01	23.38	11.90	11.51	3.22
Pd(PPHoCB)₂	Brown	646.000	84.52	245	16.41	48.30	2.79	21.67	17.00	0.341	-
Cu(PPHoCB)₂	Green	603.000	77.67	238	10.5	51.69	2.98	23.2	11.80	0.489	1.86
Zn(PPHoCB)₂	Colorless	605.400	83.85	251	10.8	51.54	2.97	23.13	11.70	0.249	-
Cd(PPHoCB)₂	Colorless	653.800	84.38	256	21.42	47.76	2.77	17.19	10.85	0.997	-
Hg(PPHoCB)₂	Colorless	740.590	81.96	263	27.09	42.13	2.43	18.9	9.59	0.679	-

Spectral Studies

FT(IR) Spectra

The bonding of the HPPHoCB ligand to transition metal ions was analysed by comparing the FT(IR) spectra of the synthesised complexes to those of the free HPPHoCB ligand (Table-2). Some significant bands were chosen to study the influence of HPPHoCB ligand vibration on transition metal complexes. The absence of stretching vibrations due to the aldehyde ν(CHO) and amino ν(NH₂) moiety of hydrazide confirms the development of the HPPHoCB ligand, and instead a strong new band formed at 1655 cm^− 1 corresponding to the azomethine ν(HC = NN-) group [22]. After complexation, the band due to azomethine vibration moved to a lower frequency of 1579–1588 cm^− 1, showing that the azomethine-N was coordinated to metal ions [23–24]. The HPPHoCB ligand has a distinctive strong band at 3187 cm^− 1, which is attributed to aromatic ν(N-H), which disappears in metal complex spectra, confirming deprotonation and coordination of the pyrrole group [25]. This is further confirmed by the appearance of a lower frequency band at 600–608 cm^− 1 in metal complexes as a result of (M–N) [26–30]. A broad band identified as aliphatic (NH) in the range of 3195–3289 cm^− 1 suggests the presence of the HPPHoCB ligand as well as the complexes [31–32]. All of the compounds attributed to ν(M→N) include metal ligand bands in the 572–599 cm^− 1 and 510–555 cm^− 1 regions [33–34].

Table-2

FT(IR) spectral data of HPPHoCB ligand and its metal complexes

Comp	NH (Ali)	NH (Aro)	C-H (Aro)	C-H (aldehyde)	>C = N- (aro)	.C = N- (ali)	C-N (aro amine)	N-N- (ali)	C-Cl	o–di sub benzene ring	M-N/M→N
HPPHoCB	3281	3187	3058	2896	2070	1655	1311	1009	900	739	-
Cr(PPHoCB)₃	3197	-	3058	2986	2011	1580	1309	1087	915	729	600, 552, 514
Mn(PPHoCB)₂	3203	-	3060	2986	2014	1581	1324	1021	860	730	623, 550, 515
Fe(PPHoCB)₂	3202	-	3060	2983	2013	1583	1316	1023	859	729	583, 543, 515
Co(PPHoCB)₂	3197	-	3059	2979	1999	1579	1307	1088	859	729	602, 552, 512
Ni(PPHoCB)₂	3195	-	3059	2980	2000	1579	1304	998	859	728	602, 552, 520
Pd(PPHoCB)₂	3194	-	3060	2980	2014	1578	1306	1004	858	728	600, 548, 510
Cu(PPHoCB)₂	3287	-	3061	2980	2000	1586	1311	1022	870	735	599, 555, 511
Zn(PPHoCB)₂	3201	-	3060	2980	1998	1588	1321	982	876	753	608, 535, 521
Cd(PPHoCB)₂	3279	-	3062	2888	2018	1581	1279	996	887	723	608, 534, 513
Hg(PPHoCB)₂	3289	-	3060	2980	1998	1584	1315	1043	905	723	572, 536, 511

¹ H NMR Spectra

Table-3 shows the ¹H NMR spectral data of the HPPHoCB ligand and its Mn(II), Pd(II), Zn(II), Cd(II), and Hg(II) complexes. The aromatic NH proton can be assigned to the signal at δ12.968 in the spectrum of free HPPHoCB ligand [35]. This signal vanished in the spectra of metal complexes containing Pd(II), Zn(II), Cd(II), and Hg(II), confirming the coordination of the HPPHoCB ligand to the metal ion via the deprotonated pyrrole group. Signals at δ8.496–8.770 and δ8.404–8.525 in the spectrum of HPPHoCB ligand are ascribed to -CH = and aliphatic NH protons, respectively [36–37]. The aromatic protons in the HPPHoCB ligand and its metal complexes range from δ7.545 to 8.060 ppm [38–40].

Table-3

¹H NMR spectral data of HPPHoCB ligand and its metal complexes

Comp	NH (aro)	CH (ali)	NH (Ali)	Aromatic Protons
HPPHoCB	12.968	8.649	8.464	7.548–8.044
Mn(PPHoCB)2	-	8.65	8.457	7.550–8.05
Pd(PPHoCB)2	-	8.651	8.465	7.550–8.050
Zn(PPHoCB)2	-	8.644	8.475	7.550–8.051
Cd(PPHoCB)2	-	8.725	8.467	7.550–8.050
Hg(PPHoCB)2	-	8.77	8.45	7.550–8.05

Magnetic Moment Measurements And Electronic Spectra

The electronic absorption spectra of the ligand and the complexes were recorded in chloroform in the region 200–900 nm. The observed electronic transitions and calculated ligand field parameters of the metal complexes are listed in Table-4. The electronic spectra provided enough information regarding the arrangements of the ligand around the central metal ions. The spectrum of the ligand shows two bands at 410, 285 and 230 nm which are attributed to π→π* transitions. In the electronic spectra of the complexes, intra-ligand π→π* transitions appear in the region 235–291 nm [41]. Bands appearing in all metal complexes at 420–485 nm are assigned to the ligand to metal charge transfer transitions [42].

The electronic spectrum of [Cr(PPHoCB)₃] complex showed two bands at 555nm and 445nm assignable to ⁴A_2g(F) → ⁴T_2g(F)(ν₁) and ⁴A_2g(F) → ⁴T_1g(F)(ν₂) transitions, respectively in an octahedral geometry being assumed [43]. The ⁴A_2g(F) →⁴T_1g(P)(ν₃) band expected to be at ca. 430nm in UV region, generally was hidden by the broad charge transfer band. Racah interelectronic repulsion parameter (B) is calculated according to the formula [44].

B = (2ν₁² − 3ν₁ν₂ + ν₂²/(15ν₂ − 27ν₁).

And from this, values of nephelauxetic parameter (β) are computed as β = B/B^o (B^o for free Cr(III) ion = 918 cm^− 1 ). The calculated Dq, B, β and ν₂/ ν₁ values as well as the magnetic moment (3.87 B.M.) confirm an octahedral environment around Cr(III) ion [45–46].

Magnetic susceptibility measurement of the Fe(II) complex was made at room temperature, which indicate that the Fe(II) complex was paramagnetic, corresponding to 2 + oxidation state of iron in this complex. The electronic spectrum of the Fe(II) complex displayed absorption band at 660 nm which were assigned to ⁵T_2g→⁵E_g transition [47]. Also, the band at 455, 420 and 395 nm are assigned to L → M charge transfer. The Fe(II) complex had a magnetic moment value of 5.51 B.M. which was consistent with high spin octahedral geometry [48–51].

Co(II) complex of HPPHoCB at room temperature shows magnetic moment 4.51 BM. This value is in good agreement with those reported for octahedral Co(II) complexes [52]. The Co(II) complex exhibited two distinct absorptions at ∼900nm and 510nm assigned to ⁴T_1g(F) →⁴T_2g(F) (ν₁) and ⁴T_1g(F) →⁴T_2g(P) (ν₂), respectively, which suggests octahedral geometry around the Co(II) ion [53]. ν₃ is not observed, but it is calculated by appropriate equation [54], which is very close to metal to ligand charge transfer transition [55–56].

The Ni(II) complex reported herein are high spin with room temperature magnetic moment value 3.22 BM, which is in the normal range observed for octahedral complexes [57–59]. The electronic spectra of Ni(II) complex displayed two bands at 978 and 610nm, assigned to ³A_2g(F)→ ³T_2g(F) (ν₁) and ³A_2g(F) → ³T_1g(F) (ν₂), transitions, respectively [60]. These are the characteristic bands of octahedral environment around Ni(II) ion. The Band-fitting equations [61] have been used to calculate the and third transition ³A_2g(F)→ ³T_1g(P) (ν₃) and ligand field parameters (Dq, B, β, and β%) for Co(II) and Ni(II) complexes indicated significant covalent character of metal ligand bonds (Table-4). The value of Racah parameter (B) is less than free ion value, suggesting an orbital overlap and delocalization of electron on the metal ion. The nephelauxetic ratio (β) for the metal complexes is less than one suggesting partial covalency in the metal ligand bond [62–64].

The copper complex of HPPHoCB ligand shows bands at 635, which can be assigned to ²B_1g → ²A_1g (ν₁) transition. It is a characteristic band of square planar geometry around the Cu(II) [65]. The room temperature magnetic moment value 1.86 falls in the range normally observed for square planar complexes [66]. Electronic spectra of homo-binuclear [Mn(PPHoCB)₂] complex exhibited weak absorption bands in the range 423 and 515nm and these bands were assigned as ⁶A_1g → ⁴E_g(⁴D), and ⁶A_1g → ⁴T_1g(⁴P) transitions, respectively, which is concordant with octahedral geometry of the metal complexes [67]. The observed magnetic moment value (6.10BM) also supported high spin octahedral geometry for [Mn(PPHoCB)₂] complex [68–69].

The electronic spectra of Pd(II), Zn(II), Cd(II) and Hg(II) complexes show intense bands at region 402–425, 353–375 and 222-298nm which are assigned to the intra ligands N → M(II) and N-M(II) LMCT, respectively. These spectral features indicate the bonding of HPPHoCB to the M(II) via nitrogen atom [70–72].

Table-4

Electronic spectral data of HPPHoCB ligand and its metal complexes

Compound	λnm	Transition
HPPHoCB	410	π→π∗
	285	π→π∗
	230	π→π∗
Cr(PPHoCB)₃	555	⁴A_2g(F) → ⁴T_2g(F)(ν₁)
Cr(PPHoCB)₃	445	⁴A_2g(F) → ⁴T_1g(F)(ν₂)
Mn(PPHoCB)₂	515	⁶A_1g → ⁴T_1g(⁴P)
Mn(PPHoCB)₂	423	⁶A_1g → ⁴E_g(⁴D)
Fe(PPHoCB)₂	660	⁵T_2g→⁵E_g
Fe(PPHoCB)₂	455, 420, 395	L → M charge transfer
Co(PPHoCB)₂	∼900	⁴T_1g(F) →⁴T_2g(F) (ν₁)
Co(PPHoCB)₂	510	⁴T_1g(F) →⁴T_2g(P) (ν₂)
Ni(PPHoCB)₂	978	³A_2g(F)→ ³T_2g(F) (ν₁)
Ni(PPHoCB)₂	610	³A_2g(F) → ³T_1g(F) (ν₂)
Pd(PPHoCB)₂	425, 375, 298	L → M charge transfer
Cu(PPHoCB)₂	635	²B_1g → ²A_1g (ν₁)
Zn(PPHoCB)₂	411, 366, 291	L → M charge transfer
Cd(PPHoCB)₂	405, 353, 238	L → M charge transfer
Hg(PPHoCB)₂	402, 360, 222	L → M charge transfer

Esr Spectra

To understand the stereochemistry of [Cu(PPHoCB)₂], the electronic spin resonance spectrum was recorded in a solid state at liquid nitrogen temperature. The ground state can be calculated using the [Cu(PPHoCB)₂] complex's g-tensor values (g_|| = 2.12, g_⊥ = 2.05, g_ave = 2.07, G = 2.46) [73–74]. In square planar complexes, the unpaired electron is in the d_x2−y2 orbital, resulting in ²B_1g as the ground state with g_|| > g_⊥ > 2, whereas the unpaired electron is in the d_z2 orbital, resulting in ²A_1g as the ground state with g_|| > g_⊥ > 2. Because g_|| > g_⊥ > 2 in this scenario, the unpaired electron is most likely in the d_x2−y2 orbital, implying square planar geometry surrounding the copper(II) ion [75–76]. There was no signal at half field in the spectrum, ruling out the idea of a dimeric form [77].

X-ray Diffraction

The X-ray diffraction of the homo-binuclear metal complexes was scanned in the 2θ range of 10–80˚ at wavelength 1.5406. The associated data of diffractogram depict the 2θ value for each peak, relative intensity and interplanar spacing (d-values). By using Scherer’s formula, the average crystallite size (dxrd) of the metal complexes was calculated. The XRD patterns exhibited sharp crystalline peaks which specify the crystalline phase of metal complexes [78]. The Cu(II), Co(II), Ni(II) and Mn(II) Schiff base metal complexes have an average crystallite size of 1, 21, 45 and 41 nm respectively. The h2 + k2 + l2 values were Cr(III), Fe(II), Co(II), Ni(II) and Cu(II). The calculated lattice parameter for metal complexes is a = b = c = 7.5, 7.04, 6.59 and 3.18. The observed values of the metal complexes may belong to octahedral systems [79–81].

Biological Studies

Antibacterial studies

The antimicrobial activities of the synthesized HPPHoCB ligand and its metal complexes were screened in vitro against diverse bacteria and fungi strains are shown in Tables-5 & Table-6 respectively. In general, the antibacterial screening data reveal that all the compounds were active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa with zones of inhibition ranging in between 16.9 and 30.5 mm. Also, all the metal complexes were active against Staphylococcus aureus with greater inhibitory values (20.87–30.5 mm), than HPPHoCB ligand (5.9mm). This expectation is traceable to chelation theory effect [82], which decreases the polarity of the metal atom due to partial sharing of its charge with donor groups of the ligand and the possibility of π-electron delocalization over the whole chelate rings, leading to increase in lipophilic character that allows permeation into the bacterial membrane’s lipid layers. The ligand was more sensitive against Bacillus subtilis than the complexes, except Mn(II) complex with zone of inhibition values 16.3 mm. In addition, Hg(II) complex had the highest inhibitory zone value of 30.52 mm against Escherichia coli compared to other compounds and even the reference drug, streptomycin with 22.0 mm (Table-5). The higher value exhibited by Hg(II) complex may be attributed to the bioactivity and biotoxicity of Hg²⁺ metal in coordination with the ligands, leading to easy penetration into the cell-lipid membrane, which obstruct and destroy the respiration process of the test organism [83]. The Hg(II) complex in comparison to all other complexes, is more toxic and effective towards the microbes- Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa with inhibitory zone values of 30.8, 26.7, 30.52 and 20.1 mm respectively, and to the standard (streptomycin) with respective inhibition values of 22.0, 21.42 22.0 and 24.0 mm. Result of this kind, in which test compounds have greater antibacterial efficacy than the standard- streptomycin has been reported [84–85].

Table-5

Antibacterial studies of HPPHoCB ligand and its metal complexes

Compound	Antibacterial Activity (zone of inhibition)
Compound	S. aureus	B. subtilis	E. coli	P. aeruginosa
HPPHoCB	5.90	16.90	15.21	13.09
Cr(PPHoCB)₃	20.32	19.55	19.35	20.98
Mn(PPHoCB)₂	19.54	16.30	18.56	16.56
Fe(PPHoCB)₂	20.87	15.21	20.18	19.99
Co(PPHoCB)₂	22.63	19.35	20.99	20.98
Ni(PPHoCB)₂	25.67	18.56	22.60	12.76
Pd(PPHoCB)₂	19.47	25.63	21.23	14.55
Cu(PPHoCB)₂	20.98	24.45	19.90	19.57
Zn(PPHoCB)₂	16.56	23.78	18.50	20.67
Cd(PPHoCB)₂	19.99	19.03	19.60	22.69
Hg(PPHoCB)₂	30.80	26.70	30.52	20.10
Streptomycin	22.00	21.42	22.00	24.00

Antifungal Studies

The antifungal studies showed that the ligand and its complexes that were active against the three fungi- Aspergillus niger, Aspergillus flavous and Fusarium species in most cases, possess almost two and half times potency (22.9–35.6 mm) compared to the standard fluconazole (11.3–15.9 mm), except only Mn(II) complex with (9.8 mm) zone of inhibition very close to that of fluconazole (11.3 mm) against Aspergillus flavous (Table − 6). The transition complexes of were resistant to the Aspergillus niger, and Aspergillus flavous. Interestingly, all the compounds were more active (29.6–35.0 mm) compared to the reference drug (13.9 mm) against Fusarium species, with the chelates having larger values of inhibition in the range 31.9–35.0 mm than the ligand with inhibitory zone values range 10.3–10.7 mm, corroborating effect of Tweedy’s chelation theory [85–86]. The results revealed Cr(III) complex to be the best with highest fungicidal activities compared to other complexes against the three fungi.

Table-6

Antifungal studies of HPPHoCB ligand and its metal complexes

Compound	Antibacterial Activity (zone of inhibition)
Compound	Aspergillus niger	Aspergillus flavous	Fusarium species
HPPHoCB	10.60	10.30	10.70
Cr(PPHoCB)₃	30.32	19.55	32.35
Mn(PPHoCB)₂	29.54	9.80	33.66
Fe(PPHoCB)₂	30.87	25.21	31.18
Co(PPHoCB)₂	33.78	29.35	31.99
Ni(PPHoCB)₂	34.57	23.67	34.60
Pd(PPHoCB)₂	29.47	25.63	31.90
Cu(PPHoCB)₂	20.98	22.90	32.25
Zn(PPHoCB)₂	29.60	23.78	33.58
Cd(PPHoCB)₂	30.22	29.03	32.78
Hg(PPHoCB)₂	35.00	35.60	35.0
Fluconazole	15.9	11.30	13.9

In Vitro Cytotoxicity

It is evident from the data recorded in Table-7 that all prepared transition complexes displayed cytotoxic activity with LD₅₀ = 2.178–8.439 × 10^− 4 M/mL, against Artemia salina, while the HPPHoCB ligand was inactive for this assay [87–90].

Table-7

Brine shrimp bioassay of HPPHoCB and their metal (II/III) complexes

Compound	LD₅₀ (M)
HPPHoCB	-
Cr(PPHoCB)₃	> 2.178 × 10^− 4
Mn(PPHoCB)₂	> 3.45 × 10^− 4
Fe(PPHoCB)₂	> 6.11 × 10^− 4
Co(PPHoCB)₂	> 3.78 × 10^− 4
Ni(PPHoCB)₂	> 4.57 × 10^− 4
Pd(PPHoCB)₂	> 8.49 × 10^− 4
Cu(PPHoCB)₂	> 4.57 × 10^− 4
Zn(PPHoCB)₂	> 5.91 × 10^− 4
Cd(PPHoCB)₂	> 7.05 × 10^− 4
Hg(PPHoCB)₂	> 4.75 × 10^− 4

In this paper, we have explored the synthesis and coordination chemistry of some mononuclear complexes derived from the pyrrolopyrimidine ligand. It containing various transition metal complexes such us Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Pd(II), Cu(II), Zn(II), Cd(II), and Hg(II) were synthesized and evaluated, their antimicrobial & cytotoxic activities were determinates. According to the electronic, IR and NMR spectral data of the azomethine linked oxime ligand, the complexes coordinated to the metal ion through the pyrrolo, pyrimidine and hydrazide nitrogen atoms of the prepared ligand. Based on the obtained results, the structure of the coordination compounds under investigation can be formulated as in Scheme-2.

All synthesised metal complexes demonstrated remarkable antimicrobial activity as a result of metal chelation with organic ligands, which increased their effect synergistically. This increased activity of all metal complexes after chelation is attributed to Tweedy's chelation theory, which states that chelation reduces the polarity of the metal atom primarily due to the positive charge of the metal being partially shared with donor atoms present on the ligand and that there is electron delocalization throughout the entire chelate ring. As a result, the metal chelates became more lipophilic, allowing it to pass through the lipid layers of bacterial membranes.

It is thought that the chelated complexes deactivate various cellular enzymes that are important in these microorganisms' metabolic pathways. Other factors affected by the presence of metal ions, such as solubility, conductivity, and dipole moment, may also increase the biological activity of metal complexes compared to the ligand. All prepared complexes (1–10) show significant cytotoxicity on the sensitive cell lines. Results of this integrated effort directly aid the efficacy of the synthesised metal complexes in inhibiting the Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Artemia salina which opens new venues to further developing these complexes up to antimicrobial and cytotoxic lead candidates.

Competing interests

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.

Ethical approval

Authors declare no conflict of interest. This article does not involve any animal experiment or human subject experiment. All the descriptions in this manuscript are accurate and agreed by all authors in such a manner to meet the standard of the Journal (Research on Chemical Intermediates).

Author contributions

AB contributed in experimental research, writing—original draft, formal analysis. YP helped in characterization, writing—original draft. DD contributed to writing review and editing, supervision. All authors have given approval to the final version of the manuscript.

Funding

There are no financial resources.

Availability of data and materials

The datasets generated and/or analyzed in the course of the current study are available from the corresponding author on reasonable request.

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Schemes are available in Supplementary Files section.

No competing interests reported.

GraphicalAbstract.png
Scheme1.png
Scheme-1: Preparation of HPPHoCB ligand
Scheme2.png
Scheme-2: Preparation of HPPHoCB Metal Complexes

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Synthesis and Characterization of Some Transition Complexes with 4- [2-(2-chlorobenzylidene)hydrazinyl]-7H-pyrrolo[2, 3-d]pyrimidine: Antimicrobial and Cytotoxic Activity

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Abstract

Introduction

Experimental

Materials And Methods

Physical Measurements

Synthesis

Synthesis of the HPPHoCB ligand

Synthesis Of Metal Complexes Of 4-[2-(2-chlorobenzylidene) Hydrazinyl]-7h-pyrrolo[2,3-d]pyrimidine (Hpphocb)

Antimicrobial Assay

Test Microorganisms

Antibacterial Activity

Determination Of Minimum Inhibitory Concentration (Mic)

Antifungal Activity

In Vitro Cytotoxicity

Results And Discussion

General Studies

Spectral Studies

FT(IR) Spectra

Magnetic Moment Measurements And Electronic Spectra

Esr Spectra

X-ray Diffraction

Biological Studies

Antibacterial studies

Antifungal Studies

In Vitro Cytotoxicity

Conclusion

Declarations

References

Schemes

Additional Declarations

Supplementary Files

Status:

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