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Article

Synthesis, X-ray Diffraction and Computational Druglikeness Evaluation of New Pyrrolo[1,2-a][1,10]Phenanthrolines Bearing a 9-Cyano Group

by
Mihaela Cristea
1,
Marcel Mirel Popa
1,*,
Sergiu Shova
2,
Maria Gdaniec
3,
Amalia Stefaniu
4,
Constantin Draghici
1,
Mihai Raduca
1,5,
Nicoleta Doriana Banu
1 and
Florea Dumitrascu
1,*
1
“C. D. Neniţescu” Institute of Organic and Supramolecular Chemistry, Romanian Academy, 202 B Splaiul Independenţei, 060023 Bucharest, Romania
2
Department of Inorganic Polymers, Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica Vodă nr. 41A, 700487 Iaşi, Romania
3
Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland
4
National Institute of Chemical Pharmaceutical Research and Development—ICCF, 112 Vitan Av., 031299 Bucharest, Romania
5
Inorganic Chemistry Department, Faculty of Chemistry, University of Bucharest, Regina Elisabeta Blvd., 4-12, 030018 Bucharest, Romania
*
Authors to whom correspondence should be addressed.
Symmetry 2024, 16(7), 911; https://doi.org/10.3390/sym16070911
Submission received: 28 June 2024 / Revised: 12 July 2024 / Accepted: 15 July 2024 / Published: 17 July 2024
(This article belongs to the Special Issue Symmetry/Asymmetry of Molecules Related to Biological Activity)
Browse Figures
Versions Notes

Abstract

:
New 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–d, obtained by a 1,3-dipolar cycloaddition reaction between the corresponding N-ylides of 1,10-phenanthrolinium bromides 2a–d, generated in situ and acrylonitrile as a dipolarophile, were investigated by single-crystal X-ray diffraction and computational studies to assess their druglikeness and evaluate their structure-activity properties. The non-covalent interactions present within the supramolecular landscape of the new 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines were correlated with the SAR investigations with the aim of estimating the propensity for bioactivity in these compounds.

1. Introduction

The derivatives of fused polyazaheterocycles, known for their wide range of biological activities, are of considerable interest due to their extensive applications in medicinal chemistry [1]. In order to increase the structural diversity of biologically active compounds, through structural combination strategies that aim to assemble different pharmacophores in the same molecular framework, several series of fused pyrrolophenanthrolines have been reported so far in the literature as possessing both biological impact and other interesting properties [2].
Fused pyrrolo[1,10]phenanthroline derivatives have attracted the attention of researchers, with the chemistry, synthesis methods and properties of these N-heterocycles being studied by several research groups [3,4,5,6,7]. These polycyclic compounds are very interesting molecules, with biological [8,9,10,11,12,13,14], electrical [15,16,17] or optical [18,19] properties.
The great potential of functionalization of phenanthroline or chemical transformation to more complex polycyclic compounds is also known, one example being their utilization in the obtaining of helicenes, polycyclic compounds displaying helical chirality [20,21,22,23,24,25,26,27,28,29].
Our on-going objective was the application of 1,3-dipolar cycloaddition of cycloimmonium N-ylides to obtain pyrrolo-fused nitrogen heterocycles, and thus phenanthroline was a remarkable building block for constructing interesting new structures [10,20,24,25,26,27,30,31,32,33,34,35,36,37]. The synthesis of such structures is rather limited to a few strategies [2,21,26,34,38,39,40,41,42,43,44].
The literature data show few reports on the biological activity of pyrrolo[1,2-a][1,10]phenanthroline derivatives [37,45]. Moreover, the cyano group is among the interesting pharmacophores to be investigated [46,47,48].
In silico investigations on physicochemical properties and pharmacokinetics are widely employed in medicinal chemistry to assess the potential of a small molecule to become an active therapeutic agent against specific targets, depending on their interaction strengths and binding affinity. Density Functional Theory (DFT) methods are used to predict properties [49] and key molecular descriptors and parameters related to pharmacokinetics and bioavailability [50,51] to rationally design new molecules with enhanced potential and specificity against various diseases. In drug development, the pharmacokinetics properties, such as absorption, distribution, metabolism and excretion (ADME profile), of drug candidates can be predicted using computational tools for specific molecular parameters which must comply with pre-established rules [52,53].
Herein we present some structural aspects of nitrile functionalized pyrrolo[1,2-a][1,10]phenanthroline, which can indicate their potential for in-depth pharmaceutical screening based on the nitrile pharmacophore group, their binding properties and non-covalent interactions of such compounds extracted from their interesting crystallographic structures.

2. Materials and Methods

2.1. Chemicals and Instrumentations

Melting points were measured on a Boëtius hot plate apparatus and are uncorrected. The 1H and 13C-NMR spectra were recorded on a Varian Gemini 300 BBat 300 MHz for 1H and 75 MHz for 13C. Chemical shifts (δ) are given in parts per million (ppm); the homo- and heterocoupling patterns (J) are given in hertz (Hz). The chemical shifts were measured against the residual solvent peak as reference.
All starting materials or solvents are commercially available and were used without further purification.

2.2. Synthesis and Characterization of Compounds 5a–c

Synthesis of 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines:
A mixture of 1,10-phenanthrolinium bromide 2a–c (5 mmol), acrylonitrile (15 mmol), and Et3N (6 mmol) and tetrakis-pyridino-cobalt (II) dichromate (TPCD, 5 mmol) in DMF (30 mL) was stirred at 80–90 ◦C for 6 h. After cooling the resulting mixture to room temperature, a 5% (v/v) aqueous HCl solution (100 mL) was added. Compounds 5a–c were obtained as precipitates, filtered and subsequently purified by crystallization from nitromethane, resulting in the 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–c in good yields.
11-(4-Methylbenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carbonitrile (5a)
Yellow platelet-shaped crystals obtained from acetonitrile, m.p. 259–261 °C; yield 57%. Elemental analysis: found for C24H15N3O: C, 79.98; H, 4.51; N, 11.92. Calculated: C, 79.76; H, 4.18; N, 11.63. 1H-NMR (CDCl3; δ, ppm; J, Hz): 2.51 (s, 3H, Me); 7.34–7.41 (m, 4H, H-3, H-10, H-3′, H-5′); 7.74 (d, 1H, 9.1, H-7); 7.85 (d, 1H, 8.5, H-5); 7.90 (d, 1H, 8.5, H-6); 7.92 (d, 1H, 9.1, H-8); 8.10–8.24 (m, 4H, H-2, H-4, H-2′, H-6′). 13C-NMR (CDCl3; δ, ppm): 21.8 (Me); 84.9 (C-9); 116.0 (CN); 117.8 (C-8); 121.2 (C-10); 122.8 (C-3); 125.5, 127.8, 129.6, 133.5, 137.7, 140.6 (C-4a, C-6a, C-8a, C-11, C-12a, C-12b); 125.6 (C-5); 126.0 (C-6); 126.5 (C-7); 129.2 (C-3′, C-5′); 130.3 (C-2′, C-6′); 134.4 (C-1′); 143.6 (C-4′); 135.9 (C-4); 146.3 (C-2); 184.4 (CO).
11-(Biphenylcarbonyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carbonitrile (5b)
Yellow platelet-shaped crystals obtained from acetonitrile, m.p. 231–233 °C; yield 50%. Elemental analysis: found for C29H17N3O: C, 82.63; H, 4.39; N, 10.33. Calculated: C, 82.25; H, 4.05; N, 9.92. 1H-NMR (CDCl3; δ, ppm; J, Hz): 7.39–7.54 (m, 5H, H-3, H-10, H-3″, H-4″, H-5″); 7.71–7.96 (m, 8H, H-5, H-6, H-7, H-8, H-3′, H-5′, H-2″, H-6″); 8.21–8.31 (m, 4H, H-2, H-4, H-2′, H-6′).13C-NMR (CDCl3; δ, ppm): 85.2 (C-9); 116.0 (CN); 118.0 (C-8); 121.5 (C-10); 122.9 (C-3); 125.7, 128.0, 129.5, 133.5, 137.8, 140.7 (C-4a, C-6a, C-8a, C-11, C-12a, C-12b); 125.7 (C-5); 126.1 (C-6); 126.7 (C-7); 127.2 (C-3″, C-5″); 127.5 (C-2″, C-6″); 128.4 (C-4″); 129.2 (C-3′, C-5′); 130.9 (C-2′, C-6′); 135.9 (C-1′); 136.1 (C-4); 140.2 (C-1″); 145.6 (C-4′); 146.5 (C-2); 184.2 (CO).
11-(4-Nitrobenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carbonitrile (5c)
Yellow platelet-shaped crystals obtained from acetonitrile, m.p. 315–317 °C; yield 55%. Elemental analysis: found for C23H12N4O3: C 70.70; H 3.39; N 14.55. Calculated: C, 70.41; H, 3.08; N, 14.28. 1H-NMR (CDCl3; δ, ppm; J, Hz): 7.36 (s, 1H, H-10); 7.45 (dd, 1H, 8.2, 4.4., H-3); 7.82 (d, 1H, 9.1, H-7); 7.91 (d, 1H, 8.8, H-5); 7.97 (d, 1H, 9.4, H-6); 8.00 (d, 1H, 9.4, H-8); 8.20 (dd, 1H, 4.4, 1.5, H-2); 8.27 (dd, 1H, 8.2, 1.5, H-4); 8.34 (d, 2H, 8.8, H-2′, H-6′); 8.40 (d, 2H, 8.8, H-3′, H-5′). 13C-NMR (CDCl3; δ, ppm): 85.8 (C-9); 115.6 (CN); 118.1 (C-8); 121.5 (C-10); 123.2 (C-3); 123.9 (C-3′, C-5′); 125.8; 128.2; 129.5; 132.3; 137.4; 140.9 (C-4a; C-6a; C-8a; C-11; C-12a; C-12b); 125.8 (C-5); 126.6 (C-6); 126.9 (C-7); 131.0 (C-2′, C-6′); 136.5 (C-4); 142.4 (C-1′); 146.3 (C-2); 150.4 (C-4′); 183.8 (CO).

2.3. X-ray Structural Analysis

Single-crystal X-ray diffraction data were collected by a XtaLAB Synergy, Dualflex, and HyPix diffractometer using Cu Kα radiation. The unit cell determination and data integration were carried out using the CrysAlisPro package from Oxford Diffraction [54]. The multi-scan correction for absorption was applied. The structures were solved with the SHELXT program using the intrinsic phasing method and refined by the full-matrix least-squares method on F2 with SHELXL [55,56]. Olex2 was used as an interface to the SHELX programs [57]. An anisotropic model was used for the refinement of non-hydrogen atoms. Hydrogen atoms were added in idealized positions and refined using a riding model. Compound 5b was crystallized as a chloroform semisolvate which was encountered before for similar structures [21]. The crystal structures are reported for two triclinic solid-state phases of this compound, the room temperature phase 5bHT and low temperature phase 5bLT at 160 K. Upon cooling, the disordered solvent molecule became ordered and the unit cell volume doubled. Selected crystallographic data and structure refinement details are provided in Table 1 and the corresponding CIF files. The supplementary crystallographic data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or [email protected]).

2.4. Computational Details

Computations regarding molecular and drug-like properties on the equilibrium geometries of the synthetized compounds were performed using Spartan v. 24 software from Wavefunction, Inc., Irvine, CA, USA [58], for the conformers showing the lowest energy of each structure, in vacuum conditions, at ground state using B3LYP [59] global hybrid density functional model with basis set 6-311 G (d, p) [60]. Evaluation of druglikeness was conducted in accordance with Lipinski’s rule of five [52] and Veber’s guidelines [53] regarding specific properties for drug candidates.

3. Results

3.1. Synthesis

The 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–c were synthesized by an efficient one-pot reaction between 1-(4-phenylphenacyl)-1,10-phenanthrolinium bromides 2a–c, acrylonitrile and triethylamine, in the presence of TPCD, as an oxidizing agent [61]. (Scheme 1) The synthesis of bromide precursors was previously reported in the literature [26] in the N-alkylation of 1,10-phenanthroline hydrate with 2′-bromo-4′-phenylacetophenones in acetone under reflux. Compounds 5a–c and the corresponding atom numbering are presented in Scheme 1.
The synthesis of novel 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–c consists of the aromatization of tetrahydro-pyrrolo[1,2-a][1,10]phenanthrolines 4a–c, relatively stable in the reaction conditions, obtained by 1,3-dipolar cycloaddition of 1,10-phenanthrolinium-N-ylides 3a–c with acrylonitrile, using TPCD as oxidizing agent [61].
The structures of the new compounds were elucidated by NMR spectroscopy, which confirmed the substituted 9-cyano pyrrolophenanthroline framework. The H-10 hydrogen atom appears as a singlet in the range 7.36–7.41 ppm. The most deshielded protons are H-2 and H-4 in the free pyridine ring of the phenanthroline system. The benzoyl moiety presents the signals of a para substitution pattern. The C atom in the CN group appears in the range 115–116 ppm. The C=O group appears in the region 183.8–184.4 ppm as the most deshielded C-atom.

3.2. X-ray Crystallography

The results of X-ray structural analyses for 5a, 5bHT, 5bLT and 5c are illustrated in Figure 1, while the geometric parameters are summarized in Table S1. Compound 5b crystallized from chloroform solution as a semisolvate. This triclinic semisolvate on cooling undergoes a phase transition to another triclinic phase with a unit cell twice as large. Upon transition, ordering of the solvent molecules takes place.
As was to be expected, by analogy with the structures of other 1-acyl-pyrrolo[1,2-a][1,10]phenanthrolines [21,28,29], all studied molecules show severe overcrowding that results in their helical structure. The fused-ring system is twisted to avoid strong steric repulsions between the atoms of the terminal pyridine ring and the benzoyl substituent at the pyrrole fragment. The degree of helicity of the fused-ring system can be estimated by a dihedral angle between the planes of the terminal rings. These dihedral angles are similar and range from 19.54° in 5bHT to 25.06° in 5c. Despite the twisting of the fused-ring system, some intramolecular contacts remain quite short, as, for example, the non-bonding distance between the pyridine N1 and the carbonyl carbon C17 (2.513(2)-2.532(2) Å) that is ca. 0.7 Å shorter than the sum of the van der Waals radii. A steric strain associated with this short distance leads to a significant displacement (0.485–0.560 Å) of the carbonyl C17 atom from the plane of the virtually planar pyrrole ring and to a pyramidal arrangement of three bonds formed by C15. The C15 atom is displaced from the plane through N2, C14 and C17 by 0.468 Å in 5a to 0.560 Å in 5bHT. Due to a helical structure, the studied molecules are chiral and their two enantiomers can be assigned as P and M. Figure 1 shows P enantiomers, except 5bHT, where both enantiomers related by the pseudo-inversion center are shown. It should be pointed out that all three compounds crystallize in centrosymmetric space groups, and therefore their crystals have to contain both enantiomeric forms of molecules (Figure S1).
All crystal structures were analysed from the point of view of short intermolecular contacts. As there are no classical hydrogen-bond donors in the studied molecules, only C-H···O, C-H···N, C-H···C and C-H···π interactions involving aromatic rings were expected among the specific intermolecular interactions influencing the crystal packing. In all cases, the carbonyl O1 atom takes part in a C-H···O contact that is shorter or equal 2.60 Å. The shortest H···O contact of 2.30 Å is found in 5bLT where the solvent CHCl3 molecule acts as a donor in hydrogen bonding. In 5a and 5c, C-H···O interactions involving the carbonyl group assemble the molecules into one-dimensional supramolecular arrays (Figure 2 and Figure 3) that, in 5c, are further extended into double chains by C-H···O interaction to the nitro group. In both crystalline phases of 5b, C-H···O contacts involving the carbonyl group occur within centrosymmetric dimers formed via π···π stacking interactions between the phenanthroline fragments of the fused-ring system. These dimers are further assembled into 1D-supramolecular arrays via π···π stacking involving pyrrole and phenanthroline aromatic rings with centroid-to-centroid distances of 3.646 Å and 3.903 Å (Figure S2). Stacking interactions with the centroid-to-centroid distance of 3.636 Å between the inversion-center-related phenanthroline fragments of the neighboring one-dimensional supramolecular arrays are also found in 5a. In turn, in 5c, π···π stacking interactions involving the benzene and pyrrole rings (centroid-to-centroid distance 3.635 Å) occur within the 1D supramolecular assembly formed via C-H···O interactions (Figure 3), and C-H···π interactions between the phenanthroline fragments extend these assemblies in a 2D array. Short C-H···N contacts to the nitrile group (H···N < 2.70 Å) are absent in 5a but are found in the remaining structures. In 5a and 5bHT, this interaction is generated between inversion-center-related molecules, resulting in dimers, whereas, in 5bLT, the molecules in dimer are related by the pseudoinversion center and the two H···N distances of 2.44 and 2.64 Å differ significantly (Figure 1c).

3.3. Hirshfeld Surface Analysis

Hirshfeld surfaces (HF) [62] generated for compounds 5a–c using CrystalExplorer [63] visually display the main interactions in the supramolecular structures. The red spots in dnorm mode present the locations of the non-covalent contacts with distances under the van der Waals radii. The most relevant interactions represented by red spots (contact distances below the sum of the vdW radii) and are mainly visible (Figure 4) for the hydrogen bonds discussed in the X-ray chapter but also for short C···C or H···C contacts (π-stacking or C-H···π). For compounds 5a and 5bLT, the Shape index surfaces present the complementary spots specific for π···π interactions involving the inner rings (II and III) of the pyrrolophenanthroline skeleton. This is enhanced by the curvedness surfaces, which confirm that the two rings are the most planar (Figure 4). Compound 5c, however, does not present π···π contacts in the Shape index surface (Not shown here), even if the Hirshfeld present two red spots for short C···C contacts. These contacts might be enforced by the other strong non-covalent contacts, the distances between the ring III and ring I being 3.635 Å and the dihedral angle between the ring planes being 14.46◦. However, for such a small angle and distances, one might consider a π···π interaction to occur.
The most numerous contacts, as extracted from the Hiershfild surface, are statistically H···H contacts, which are similar (Figure 5) for 5a and 5bLT and present the same ratios for all the evaluated contacts. However, 5c, due to the introduction of the NO2 group, presents a steep decrease in H···H contacts and an increase in O···H contacts from around 7–8% for 5a,b to 25.5% for 5c. The statistical landscape of interactions in the Hirsfeld surface is a qualitative description and not a quantitative one. For example, N···H contacts are the strongest in compound 5b, which presents the lowest percentage of interactions (10.6% compared to 13.3%-5a and 12.7%-5c). However, the HF surfaces and fingerprint plots are important descriptors of possible binding modes of such molecules in view of their further evaluation as potential bioactive molecules. There is no difference between the two helical enantiomers P and M in the HF percentages, with the exception of 5bLT, where one enantiomer shares more Cl···H contacts with the chloroform solvent.
An interesting aspect in the crystal landscape of such compounds is the presence of helical chirality devising the presence of the P and M helicoidal enantiomers (Figure 6). As in the case of many helicene-like molecules, this helical chirality is induced by the presence of four or more than four ortho-condensed rings [22,64]. In structures with less condensed rings, such as pyrrolophenanthrolines, the helicoidal shape of the molecules can be induced by the presence of bulky substituents in the “Bay-region” of the molecule [21].
However, in the case of pyrrolophenanthrolines, intriguing intramolecular short-contacts were observed [27,29] between the nitrogen in ring IV and the carbon atom in the C=O from the benzoyl moiety, raising the intuition that the pitch of the helix can be influenced by an interplay of this apparently attractive force and the repulsion forces generated by the molecular strain. In this case, this non-covalent interaction might be of type lp-π between the free electrons of the N atom and the empty π-orbital of the C=O group. Such kinds of bonds are typical, for example, in protein folding due to C=O···C=O interactions [65] (where one lp is donated by O instead of N). We measured the effect of this interaction using the value of the dihedral angle between the rings I and IV versus the contact distance between the N and C atom from C=O (Table 2). The results were not very conclusive, but it appears that such kinds of interactions can be further investigated as the measured contact lengths compared to sum of vdW radii could imply strong interactions. Another conceptual proof of this interaction might be given by the deformation of the carbonyl bond with the C atom going outside the C=O bond (pyramidalization). Also, a strong H-bond in the structure of CSD: ZIPQUM [38] leads to an increase in the molecular deformation. However, the negative correlation of the data in Table 2 shows that other effects are to be considered also.
The helicoidal distortion of the molecules can influence the pitch of the helix and thus the structural similarity with bioactive molecules, such was the recent case of cholchicine mimick [5]-helistatin, the first known helicene showing real bioactive potential in relation with actual commercial drugs [66].

3.4. Druglikeness Assessment

In Figure 7, the representation of the electrostatic potential maps is given, varying from blue (the most positive values) to red (the most negative values). The potential increases in the order: red < orange < yellow < green < blue. For structure 5a, values of the electrostatic potential range from 141.24 kJ·mol−1 to −209.66 kJ·mol−1, for 5b, between 130.72 kJ·mol−1 and −208.91 kJ·mol−1, and for 5c, the values vary from 157.19 kJ·mol−1 to −194.19 kJ·mol−1. The less negative regions are overlapping the oxygen atoms.

3.5. Quantum Reactivity Parameters Calculated from FMO Predicted Energy Levels

Regarding the molecular properties assessment, in order to evaluate the potential suitability of compounds for further development, from the point of view of druggability and oral bioavailability, by applying property filters stated by Lipinski’s rule of five (RO5), it can be observed that all structures, except 5c, exhibit one violation to RO5 in terms of hydrophilicity/lipophilicity balance, as shown from the values of logP listed in Table 3. Values of logP greater than five suggest highly lipophilic compounds. This fact severely impacts on bioavailability and will require further special pharmaceutical formulations to increase the penetration in the physiological environment and to reduce the non-polar character of these compounds. Among the three structures, 5c is the most hydrophilic structure and 5b is the most hydrophobic structure, as expected, due to the phenyl substituent (R). Although other requirements of RO5 are met (mass, number of hydrogen bond donor’s and acceptors) for 5a and 5b structures, and adding the conformity with the Veber rule concerning the total polar surface area and the number of rotatable bonds, keeping in mind the fact that it represents only one minor step in drug assessment, all compounds can be further considered as leads for development and investigation of their pharmaceutical potential. Concerning the 5c compound, the replacement of the R substituent on the skeleton structure with NO2 will strongly increase the hydrophilic character and also will give the opportunity for more interactions within the active site of proteins targets due to the Lewis structure for NO2− and due to more hydrogen bond acceptors (HBA = 7).
Additionally, predictive data for the global chemical reactivity of the investigated compounds are obtained from the frontier molecular orbitals’s energy levels, as depicted in Figure 8, from their values given in Table 4. The quantum reactivity parameters are calculated according to Koopman’s’ theorem [67,68], which indicated relationships for the ionization potential (I) and the electron affinity (A) as the negative of HOMO and LUMO energies, respectively. Pearson’s Hard and Soft Acids [69,70] is basis for calculation of the softness (σ) and hardness (η) parameters. The electronic reactivity (χ) is calculated according the Maximum Hardness Principle (MHP) [70]. The electrophilicity index (ω), is obtained from an equation stated by Parr R.G and collaborators [71]. The HOMO-LUMO energy gap is a measure of the kinetic stability and reactivity of molecules. According the calculated values, among the investigated compounds, the 5b derivative seems to be the more stable, revealing the larger energy gap (3.62 eV), and 5c is the most reactive, presenting the smaller energy gap (3.23 eV).
The compounds are rather stable, and their non-covalent interactions in crystalline phase validated by the ESP provide insightful information regarding the affinity of the CN group as being pharmacophore or other possible interactions mainly driven by hydrogen bonds (given by the number of hydrogen bonds acceptors). The compounds 5a–c present large molecular masses and high logP values which might need further formulation studies in order to increase their bioavailability. Given the potential of such compounds confirmed by recent studies [8,9,10,11,12,13,14], and the potential use of the molecular distortion in mimicking commercial drugs [66], the new compounds are suitable for further expanding their structural diversity and investigating their potential anti-cancer or antibiotic properties.

4. Conclusions

In conclusion, we have synthesized and structurally characterized three new 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines and investigated their supramolecular interactions, extracted from X-ray single crystal diffraction analysis, with the aim of analyzing their potential supra-molecular binding sites and binding patterns. The helicoidal structures could present interesting properties which might infer them with bioactive properties.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/sym16070911/s1, Figure S1: Overlayed molecules illustrating the helical chirality for 5a (a), 5b (b) and 5c (c).; Figure S2: View of 2D supramolecular layer in the crystal structure 5b. H bonds and centroid-to-centroid distances are shown in dashed black and orange lines, respectively; Table S1: Bond distances (Å) and angles (°).

Author Contributions

Conceptualization, F.D., M.C. and M.M.P.; methodology, F.D., M.C. and M.M.P.; software, M.M.P., S.S. and A.S.; validation, F.D., M.C., M.M.P., S.S., M.G., A.S. and M.R.; formal analysis, F.D., M.C. and C.D.; investigation, M.M.P., S.S., M.G. and A.S.; resources, F.D. and M.C.; data curation, F.D., M.C., M.M.P., S.S., A.S., M.R. and N.D.B.; writing—original draft preparation, F.D., M.C., M.M.P., S.S. and A.S.; writing—review and editing, F.D., M.C., M.M.P., S.S. and A.S.; visualization, F.D., M.C., M.M.P., S.S., A.S. and M.R.; supervision, F.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Raw data are available from the authors upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

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Symmetry 16 00911 sch001
Scheme 1. The reaction pathway of 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–c.
Scheme 1. The reaction pathway of 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–c.
Symmetry 16 00911 sch001
Symmetry 16 00911 g001
Figure 1. The asymmetric parts in the crystal structures of 5a (a), 5bHT (b), 5bLT (c) and 5c (d) showing atom labeling and thermal ellipsoids at the 50% probability level. H-bond parameters for 5bLT: C3A-H···N3B [C3A-H 0.95 Å, H···N3B 2.64 Å, C3A···N3B 3.450(4) Å, ∠C3AHN3B 144.0°; C3B-H···N3A [C3B-H 0.95 Å, H···N3A 2.44 Å, C3B···N3A 3.280(4) Å, ∠C3BHN3A 147.7°; C1-H···O1 [C1-H 1.00 Å, H···O1 2.30 Å, C1···O1 3.232(4) Å, ∠C1HO1 155.5°.
Figure 1. The asymmetric parts in the crystal structures of 5a (a), 5bHT (b), 5bLT (c) and 5c (d) showing atom labeling and thermal ellipsoids at the 50% probability level. H-bond parameters for 5bLT: C3A-H···N3B [C3A-H 0.95 Å, H···N3B 2.64 Å, C3A···N3B 3.450(4) Å, ∠C3AHN3B 144.0°; C3B-H···N3A [C3B-H 0.95 Å, H···N3A 2.44 Å, C3B···N3A 3.280(4) Å, ∠C3BHN3A 147.7°; C1-H···O1 [C1-H 1.00 Å, H···O1 2.30 Å, C1···O1 3.232(4) Å, ∠C1HO1 155.5°.
Symmetry 16 00911 g001
Symmetry 16 00911 g002
Figure 2. View of 1D supramolecular chain in the crystal structure of 5a. H-bond parameters: C6-H···O1 [C6-H 0.95 Å, H···O1 2.60 Å, C6···O1(x − 1, 1.5 − y, 1 − z) 3.410(2) Å, ∠C6HO1 143.9°; C8-H···O1 [C8-H 0.95 Å, H···O1 2.36 Å, C8···O1(x − 1, 1.5 − y, 1 − z) 3.232(2) Å, ∠C8HO1 152.8°.
Figure 2. View of 1D supramolecular chain in the crystal structure of 5a. H-bond parameters: C6-H···O1 [C6-H 0.95 Å, H···O1 2.60 Å, C6···O1(x − 1, 1.5 − y, 1 − z) 3.410(2) Å, ∠C6HO1 143.9°; C8-H···O1 [C8-H 0.95 Å, H···O1 2.36 Å, C8···O1(x − 1, 1.5 − y, 1 − z) 3.232(2) Å, ∠C8HO1 152.8°.
Symmetry 16 00911 g002
Symmetry 16 00911 g003
Figure 3. View of 1D supramolecular chain in the crystal structure of 5c. H-bonds parameters: C1-H---O2 [C6-H 0.95 Å, H···O2 2.51 Å, C1···O2(1 − x, 1 − y, 1 − z) 3.300(2) Å, ∠C1HO2 140.9°; C14-H···O1 [C14-H 0.95 Å, H···O1 2.41 Å, C14···O1(x, 1 + y, z) 3.101(2) Å, ∠C14HO1 129.6°. Centroid-to-centroid contacts are shown in dashed orange lines.
Figure 3. View of 1D supramolecular chain in the crystal structure of 5c. H-bonds parameters: C1-H---O2 [C6-H 0.95 Å, H···O2 2.51 Å, C1···O2(1 − x, 1 − y, 1 − z) 3.300(2) Å, ∠C1HO2 140.9°; C14-H···O1 [C14-H 0.95 Å, H···O1 2.41 Å, C14···O1(x, 1 + y, z) 3.101(2) Å, ∠C14HO1 129.6°. Centroid-to-centroid contacts are shown in dashed orange lines.
Symmetry 16 00911 g003
Symmetry 16 00911 g004aSymmetry 16 00911 g004b
Figure 4. Hirshfeld surfaces of compounds 5a–c generated as dNorm, ShapeIndex and curvedness (5a).
Figure 4. Hirshfeld surfaces of compounds 5a–c generated as dNorm, ShapeIndex and curvedness (5a).
Symmetry 16 00911 g004aSymmetry 16 00911 g004b
Symmetry 16 00911 g005
Figure 5. Percentage interactions for compounds 5a–c extracted from their contribution to the HF surface. 5bHT is exemplified for information; 5bLT presents both enantiomers, as, beside the helix directions, the two enantiomers present some other particularities due to the interaction with CHCl3 solvent.
Figure 5. Percentage interactions for compounds 5a–c extracted from their contribution to the HF surface. 5bHT is exemplified for information; 5bLT presents both enantiomers, as, beside the helix directions, the two enantiomers present some other particularities due to the interaction with CHCl3 solvent.
Symmetry 16 00911 g005
Symmetry 16 00911 g006
Figure 6. Mirror image of the two helical enantiomers of compound 5a.
Figure 6. Mirror image of the two helical enantiomers of compound 5a.
Symmetry 16 00911 g006
Symmetry 16 00911 g007
Figure 7. Electrostatic potential maps for compounds 5a–c.
Figure 7. Electrostatic potential maps for compounds 5a–c.
Symmetry 16 00911 g007
Symmetry 16 00911 g008
Figure 8. FMO distribution and energy levels for compounds 5a–c.
Figure 8. FMO distribution and energy levels for compounds 5a–c.
Symmetry 16 00911 g008
Table 1. Crystal data and details of structure refinement for 5a, 5bHT, 5bLT and 5c.
Table 1. Crystal data and details of structure refinement for 5a, 5bHT, 5bLT and 5c.
Compound5a5bHT5bLT5c
Emp. formulaC24H15N3OC29H17N3O·0.5(CHCl3)C29H17N3O·0.5(CHCl3)C23H12N4O3
Fw361.39483.14483.14392.37
T [K]100293160100
space groupPbcaP-1P-1I2/a
a [Å]11.3181(2)8.0034(6)12.1617(5)24.8719(5)
b [Å]12.4550(2)12.3093(12)13.3458(5)5.80280(9)
c [Å]24.9296(4)12.4079(10)15.9128(7)27.2343(6)
α [°]9077.473(8)114.311(4)90
β [°]9078.838(7)92.757(3)116.219(3)
γ [°]9087.836(7)98.816(4)90
V [Å3]3514.25(10)1170.70(18)2308.13(18)3526.21(13)
Z8248
ρcalcd [g cm−3]1.3661.3711.3901.478
μ [mm−1]0.6810.2490.2530.835
Crystal size [mm]0.23 × 0.12 × 0.030.35 × 0.30 × 0.300.25 × 0.20 × 0.150.35 × 0.03 × 0.02
2Θ range7.09 to 133.103.42 to 50.053.38 to 50.057.24 to 133.16
Refls. collected13,62710,14221,75311,594
Indep. refls., Rint3096, 0.02814136, 0.02478145, 0.03733113, 0.0290
Data/rests./params.3096/0/2554136/0/3358145/0/6313113/0/272
GOF1.0481.0321.0261.065
R1, wR2(all data)0.0350, 0.09670.0628, 0.17400.0631, 0.16290.040, 0.0956
CCDC no.2352573235448123544822352575
Table 2. Dihedral angles vs. distance between the N atom from pyridine ring and the C=O in the benzoyl moiety.
Table 2. Dihedral angles vs. distance between the N atom from pyridine ring and the C=O in the benzoyl moiety.
CompoundDihedral Angle ◦d (C, N), Å% Sum of vdW Radii
5a21.112.52977.82
5bLT-A20.542.53277.91
5bLT-B19.802.51477.35
5c25.062.52777.75
4-CNBenzoyl [19]21.742.53277.91
Benzoyl [19]20.532.55378.55
4-MeOBenzoyl [19]20.822.55178.49
4-HexylBenzoyl [19]26.622.58579.54
AQIKER [20b]24.162.43674.95
QAQCIV [21c]18.812.51377.32
ZIPQUM [24a]25.541.851367.32
Table 3. Calculated druglike properties for the investigated structures.
Table 3. Calculated druglike properties for the investigated structures.
Property (Symbol), Units5a5b5c
Molecular weight (M) g·mol−1361.404423.475392.374
Area (A), Å2366.81431.64371.88
Volume (V), Å3370.10435.72373.26
Polar surface area (PSA), Å232.55233.00871.158
Water-octanol partition coefficient (logP)5.536.723.33
Ovality index (OI)1.471.551.48
Polarizability (α), 10−30·m370.5675.8770.89
Minimum electrostatic potential, kJ·mol−1−209.66−208.91−194.19
Maximum electrostatic potential, kJ·mol−1141.24130.72157.19
Dipole moment (D), Debye 9.797.017.92
Number of hydrogen bond donors (HBD)000
Number of hydrogen bond acceptors (HBA)447
Table 4. FMO distribution and energy levels for compounds 5a–c.
Table 4. FMO distribution and energy levels for compounds 5a–c.
ParameterFormula5a5b5c
Energy of the HOMO orbital (EHOMO), eV −5.95−5.92−6.26
Energy of the LUMO orbital (ELUMO), eV −2.40−2.30−3.03
Ionization potential (I), eVI = −EHOMO 5.955.926.26
Electron affinity (A), eVA = −ELUMO 2.402.303.03
FMO energy gap (ΔE), eVΔE = I − A3.553.623.23
Electronegativity (χ), eVχ = (I + A)/24.1754.114.645
Global hardness (η), eVη = (I − A)/2 1.7751.811.615
Softness (σ), eV−1σ = 1/η 0.5630.5530.619
Global electrophilicity index, D·eV−1ω = μ2/2η 26.99813.57519.420
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Cristea, M.; Popa, M.M.; Shova, S.; Gdaniec, M.; Stefaniu, A.; Draghici, C.; Raduca, M.; Banu, N.D.; Dumitrascu, F. Synthesis, X-ray Diffraction and Computational Druglikeness Evaluation of New Pyrrolo[1,2-a][1,10]Phenanthrolines Bearing a 9-Cyano Group. Symmetry 2024, 16, 911. https://doi.org/10.3390/sym16070911

AMA Style

Cristea M, Popa MM, Shova S, Gdaniec M, Stefaniu A, Draghici C, Raduca M, Banu ND, Dumitrascu F. Synthesis, X-ray Diffraction and Computational Druglikeness Evaluation of New Pyrrolo[1,2-a][1,10]Phenanthrolines Bearing a 9-Cyano Group. Symmetry. 2024; 16(7):911. https://doi.org/10.3390/sym16070911

Chicago/Turabian Style

Cristea, Mihaela, Marcel Mirel Popa, Sergiu Shova, Maria Gdaniec, Amalia Stefaniu, Constantin Draghici, Mihai Raduca, Nicoleta Doriana Banu, and Florea Dumitrascu. 2024. "Synthesis, X-ray Diffraction and Computational Druglikeness Evaluation of New Pyrrolo[1,2-a][1,10]Phenanthrolines Bearing a 9-Cyano Group" Symmetry 16, no. 7: 911. https://doi.org/10.3390/sym16070911

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