Crystallographic structure, activity prediction, and hydrogen bonding analysis of some CSD-based 3,3'-bis-indole derivatives: A review European Journal of Chemistry 12 (4) (2021) 493-501 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.4.493-501.2145 European Journal of Chemistry View Journal Online View Article Online Crystallographic structure, activity prediction, and hydrogen bonding analysis of some CSD-based 3,3'-bis-indole derivatives: A review Varun Sharma 1, Goutam Brahmachari 2 and Vivek Kumar Gupta 1,* 1 Department of Physics, University of Jammu, Jammu Tawi-180006, India varunsharma5228@gmail.com (V.S.), vivek.gupta2k9@gmail.com (V.K.G.) 2 Laboratory of Natural Products and Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-731235, West Bengal, India brahmg2001@yahoo.co.in (G.B.) * Corresponding author at: Department of Physics, University of Jammu, Jammu Tawi-180006, India. e-mail: vivek.gupta2k9@gmail.com (V.K. Gupta). 10.5155/eurjchem.12.4.493-501.2145 Received: 10 July 2021 Received in revised form: 18 August 2021 Accepted: 28 August 2021 Published online: 31 December 2021 Printed: 31 December 2021 Herein we report crystallographic comparison of some geometrical and structural features for a series of biologically relevant bis-indole derivatives. Selected bond distances and bond angles of interest in a series of bis-indole derivatives have been discussed in detail. The biological activity of the substances has been correlated with based the structure-activity relationships (SAR) base which provides the different possibility of activity (Pa) and possibility of inactivity (Pi). For a better understanding of the packing interactions existing among these derivatives, an overview of crystal structure analysis with emphasis on the intramolecular hydrogen bonding in some bis-indole derivatives is presented. The role of hydrogen bonding in the crystal structure assembly of bis-indole derivatives has been found to be predominant and this observation reveals significant impact of hydrogen bonding in high value of drug-likeness of these bio-molecules. Bis-indole X-ray diffraction Biological activity Hydrogen bonding Geometrical parameters Bifurcated hydrogen bonds Cite this: Eur. J. Chem. 2021, 12(4), 493-501 Journal website: www.eurjchem.com 1. Introduction Indole is the structural core unit of bis-indole derivatives, which are an important class of heterocyclic compounds having a wide variety of biological activities in both research and development of pharmaceuticals. Bis-indolylmethane deriva- tives (BIMs), mainly consist of two indole moieties connected to each other via heterocyclic units (Figure 1). These class of indole derivatives exhibits a diverse class of biological proper- ties such as antifungal, antibacterial [1], anti-implantation activities [2]. Moreover, BIMs have also been found to be potent anticancer derivatives, and clinical studies have demonstrated that they could be potentially used as chemotherapeutic agents against various forms of cancer. BIM suppresses the prolifera- tion of estrogen dependent reproductive cancers of breast [3], ovarian [4], cervical [5], and prostate [6] but also thyroid [7], neck and head [8], melanoma or blood cells (leukemia) [9]. BIMs is a potent radioprotector against UV and ionizing radiation acting by a unique mechanism of sudden activation of a nuclear kinase which regulates the response to DNA damage, repair, or apoptosis and oxidative stress [10]. Even though the most reactive site for electrophilic attack is 3-position for indole [11] but due to the competitive formation of 1,3-di-alkyl/ acylated and/or 1-acylated products, low yields are always encountered because of the ambident nature of the indole ring system. The current work provides comprehensive account of structural characteristics and packing interactions/hydrogen bonding in bis-indole derivatives. Here, we have identified a series of forty-one derivatives of bis-indole from the literature, for which an online survey of Cambridge Structural Database (CSD) has been performed. The reference code, chemical name, chemical formula, and published reference [12-53] of each molecule is presented in Table 1. N H NH 3 2 1 87 6 5 4 9 3' 2' 1' 9' 4' 5' 6' 7' 8'10 Figure 1. Basic bis-indole molecule with numbering scheme. ABSTRACT REVIEW ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.4.493-501.2145 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.4.493-501.2145 mailto:varunsharma5228@gmail.com mailto:vivek.gupta2k9@gmail.com mailto:brahmg2001@yahoo.co.in mailto:vivek.gupta2k9@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.4.493-501.2145&domain=pdf&date_stamp=2021-12-31 494 Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 1. CSD codes, chemical name, chemical formula, molecular wt. and reference of Molecule M1-41. Molecule CSD code CCDC code Chemical name Chemical formula Ref. M1 TAXTAQ 1528295 3,3'-((3,4-Dimethoxyphenyl)methylene)bis(1H-indole) C25H22N2O2 [12] M2A TEVTIY 633690 3,3'-(4-Bromophenylmethanediyl)bis(5-methoxy-1H-indole) C25H21BrN2O2 [13] M2B TEVTIY01 1511318 3,3'-[(4-Bromophenyl)methylene]bis(5-methoxy-1H-indole) C25H21BrN2O2 [14] M3 DEFMEH 233333 3,3-Bis(1H-indol-3-yl)indolin-2-one C24H17N3O·C2H6O1 [15] M4 DOPZIT 1024391 Dimethyl 3,3'-((4-chlorophenyl)methylene)bis(1H-indole-2-carboxylate) C27H21Cl1N2O4 [16] M5 EHINAM 1408303 5,5''-Dibromo-1,1'-dimethyl-1H,1''H-3,3':3',3''-terindol-2'(1'H)-one C26H19Br2N3O1 [17] M6 EMIGUE 1029492 5,5''-Difluoro-1H,1''H-3,3':3',3''-terindol-2'(1'H)-one dimethyl sulfoxide solvate C24H15F2N3O·2(C2H6OS) [18] M7 EVAKES 834300 4-(Bis(1H-Indol-3-yl)methyl)benzonitrile C24H17N3 [19] M8 GIHDUY 950651 2-(2,2-Bis(1H-Indol-3-yl)ethyl)aniline C24H21N3 [20] M9 GUCJEV 1017941 5'-Nitro-1H,1''H-[3,3':3',3''-terindol]-2'(1'H)-one dimethyl sulfoxide solvate C26H22N4O4S [21] M10 HABWOY 277162 3,3',3''-Methanetriyltris(6-methyl-1H-indole) C28H25N3 [22] M11 HODROH 135757 Bis(Indol-3-yl)(p-tolyl)methane C24H20N2 [23] M12 HOYPAN 719583 4,4-Bis(1-Benzyl-5-bromo-1H-indol-3-yl)but-3-en-2-onedimethylsulfoxide solvate C34H26Br2O·C2H6OS [24] M13 IVALEX 802362 3,3'-Ethene-1,1-diylbis(2-phenyl-1H-indole) C30H22N2 [25] M14 KEQREE 625021 5,5'-Dimethoxy-3,3'-(3-fluorophenylmethanediyl)-bis(1H-indole) C25H21FN2O2 [26] M15 KIFMES 277582 5,5'-Dimethoxy-3,3'-di-indolyl(4-(phenyl)phenyl)methane C31H26N2O2 [27] M16 LANFIS 1511319 5-Methoxy-3-((5-methoxy-1H-indol-3-yl)(4-methylphenyl)methyl)-1H-indole C26H24N2O2 [14] M17 LAWGEY 1497585 3-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-1H-indole ethyl acetate solvate C23H17ClN2·C4H8O2 [28] M18 LOKKON 946729 3,3'-(1-Naphthylmethylene)bis-1H-indole dimethylsulfoxide solvate C27H20N2·C2H6OS [29] M19 MASQAB 1532121 3-[(4-Bromophenyl)(1H-indol-3-yl)methyl]-1-methyl-1H-indole C24H19BrN2 [30] M20 MAVCUI 287459 3,3-Bis(1H-Indol-3-yl)indolin-2-one C24H17N3O [31] M21 MEDJEK 140500 1,1-Bis(Indol-3-yl)-1-phenylethane C24H20N2 [32] M22 NUQGAJ 1421585 Dimethyl 3,3'-((4-fluorophenyl)methylene)bis(1H-indole-2-carboxylate) C27H21FN2O4 [33] M23 OBABOL 1492901 3-((4-Nitrophenyl)(2-phenyl-1H-indol-3-yl)methyl)-2-phenyl-1H-indole C35H25N3O2 [34] M24 OCESAS 807664 3,3'-(Phenylmethylene)bis(5-methoxy-1H-indole) C25H22N2O2 [35] M25 ODAFAD 1408973 3,3'-((4-Methoxyphenyl)methylene)bis(1-methyl-1H-indole) C26H24N2O [36] M26 OYUXUD 1007024 3,3'-(2,2-Dimethylpropane-1,1-diyl)bis(1H-indole) C21H22N2 [37] M27 PADKUD 966140 3,3'-((4-Methoxyphenyl)methylene)bis(1-ethyl-1H-indole) C28H28N2O [38] M28 PAHSAV 1038916 3,3'-(Phenylmethylene)bis(1-ethyl-1H-indole) C27H26N2 [39] M29 PEMLUP 620698 5,5'-Dimethoxy-3,3'-(3-nitrophenylmethanediyl)bis(1H-indole) C25H21N3O4 [40] M30 PUZCAQ 956470 2,2-Bis(1H-Indol-3-yl)-1-phenylethanone C24H18N2O [41] M31 QINXAO 969227 Dimethyl 3,3'-(phenylmethylene)bis(1H-indole-2-carboxylate) C27H22N2O4 [42] M32 SESMIN 629528 3,3'-(4-Chlorophenylmethanediyl)-bis(5-methoxy-1H-indole) C25H21Cl1N2O2 [43] M33A SUVHAS 130877 3,3'-Benzylidenedi-indole C23H18N2 [44] M33B SUVHAS01 215714 3,3'-Benzylidenedi-indole C23H18N2 [45] M33C SUVHAS02 1452420 3,3'-Benzylidenedi-indole C23H18N2 [46] M34 TAGQEA 868517 3,3',3''-Methanetriyltris(1H-indole) C25H19N3 [47] M35 UNEMOR 1452423 2-Methyl-3-((2-methyl-1H-indol-3-yl)(phenyl)methyl)-1H-indole C25H22N2 [46] M36 UKAYIQ 1447737 3-(1H-Indol-3-yl(pyridin-3-yl)methyl)-1H-indole hydrate C22H17N3·0.75H2O [48] M37 UNOPOE 1481317 3-((2-Fluorophenyl)(1H-indol-3-yl)methyl)-1H-indole C23H17FN2 [49] M38 VURKIE 1060893 Ethyl bis(1-methyl-1H-indol-3-yl)acetate C34H22N12O8 [50] M39A XADJOE 1050231 3,3'-Ethane-1,1-diylbis(1H-indole) C18H16N2 [51] M39B XADJOE01 1007025 3,3'-Ethane-1,1-diylbis(1H-indole) C18H16N2 [52] M40 YOTREF 738233 3,3'-((4-Methoxyphenyl)methylene)bis(1,2-dimethyl-1H-indole) C28H28N2O [53] 2. Methodology 2.1. Crystallographic comparison The precise comparative structural parameters of all bis- indole derivatives as obtained from CSD were analysed for their crystal class, space group, the number of molecules per asymmetric unit cell, the final R-factor and are shown in Table 2. Whereas Table 3 and 4 lists the selected bond distances and bond angles of the identified molecules. 2.2. Biological activity predictions One of the most important reasons for the synthesis and structural characterization of BIMs is their potent biological and pharmacological activities. The biological activity spectrum provides us with the list of all the biological activity names which is the result of chemical substance’s interaction with different biological entities, by comparing the structure of the compound with the well-known substrate already existing in database. Prediction of Activity Spectra for Substances (PASS) software [54] is a powerful tool which provides the grounds for predicting many activity types for different compounds. The structural formula of the compound is presented as a mol. file and the predictions result us with a list of biological activities on a scale of probability ranging from 0-1. Each activity is computed on the basis of Structure-activity relationship data and knowledge base (SAR), which provides two values: Pa - the probability of the compound being active and Pi - the proba- bility of the compound being inactive for a particular biological activity. All the activities with Pa > Pi are retained as the most probable and predicted ones for a given compound. The Pa and Pi values for the molecules (M1-40) are presented in Table 5. 2.3. Molecular packing interaction analysis Hydrogen bonds is the most significant interaction having large scale application in the field of material science, crystal engineering and biological recognition due to their distinctive features i.e., strength, flexibility and directionality. In the wake of well-known documentation for strong bonds such as N-H···O and O-H···O, but weak hydrogen bonds such as C-H···N, C-H···O and C-H···X are of quiet interest due to their frequent occur- rence in organic crystal structure [55]. The knowledge of such an analysis of interactions helps us to understand the structure of bio-molecules with implication for structure-based drug design. Thus, by accumulating the research data of comparative study, we examined hydrogen-bonded interactions of the type N-H···O, C-H···O, C-H···F, N-H···N, N-H···S, and C-H···N present in bis-indole derivatives. The Crystallographic Information File (CIF) for each structure was used as an input to Mercury 4.1 software [56] for the computation of all possible hydrogen bonding interactions. Table 6 presents the data of these interactions. Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 495 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 2. Preliminary crystal data for Molecule M-1-41. Molecule Crystal system Space group R-factor Z value M1 Triclinic P-1 4.33 2 M2A Monoclinic P21/n 5.80 4 M2B Triclinic P-1 5.30 3 M3 Monoclinic P21/n 5.84 4 M4 Triclinic P-1 5.70 2 M5 Orthorhombic P212121 4.01 4 M6 Monoclinic P21/n 5.25 4 M7 Monoclinic P21/c 4.10 4 M8 Orthorhombic P212121 7.06 4 M9 Monoclinic P21 4.14 2 M10 Triclinic R-3 7.63 6 M11 Monoclinic P21/c 6.60 4 M12 Monoclinic P21/n 5.37 4 M13 Monoclinic P21/c 3.72 4 M14 Monoclinic P21/n 6.14 4 M15 Monoclinic P21/n 5.18 4 M16 Monoclinic P21/n 5.73 3 M17 Triclinic P-1 8.61 2 M18 Monoclinic P21/c 6.70 4 M19 Monoclinic P21/n 6.85 4 M20 Monoclinic C2/c 4.96 8 M21 Triclinic P-1 6.71 4 M22 Triclinic P-1 5.42 2 M23 Triclinic P-1 8.54 2 M24 Monoclinic P21/n 4.10 4 M25 Triclinic P-1 4.12 2 M26 Orthorhombic Pna21 5.02 4 M27 Monoclinic P21/c 4.34 4 M28 Triclinic P-1 5.81 2 M29 Monoclinic P21/c 6.08 4 M30 Monoclinic P21/n 6.64 4 M31 Monoclinic P21/c 6.17 4 M32 Monoclinic P21/n 6.12 4 M33A Monoclinic P21/c 5.32 4 M33B Monoclinic P21/c 6.10 4 M33C Monoclinic P21/c 6.26 4 M34 Monoclinic P21/c 3.59 8 M35 Monoclinic I2/a 5.75 8 M36 Monoclinic P21/n 7.38 4 M37 Monoclinic P21/c 3.80 4 M38 Monoclinic P21/n 6.74 2 M39A Triclinic P1 4.94 4 M39B Orthorhombic P212121 3.74 4 M40 Monoclinic P21/n 4.41 4 3. Discussion 3.1. Comparative crystallographic analysis On the basis of crystallographic data as presented in Table 2, the following observations can be made: i) Most of the identified structures of bis-indole has been crystallized in monoclinic crystal system (65.90%) followed by triclinic (25.00%), and orthorhombic (9.09%), and the most common space group of identified structure is P21/n (31.81%), followed by P21/c (27.27%) and P1 (22.72%), ii) The range of reliability index of identified structure is between 3.80-8.61% which conveys us how accurate a crystal structure is determined, iii) Degree of freedom depends on number of molecules per unit cell, Z = 4 is observed for 65.90% molecules. 3.2. Bond distance and angles All molecules undertaken contain substitutional groups at C10 positions. Therefore, it is of interest to investigate the C10- C3, C3-C2, C3-C9, C10-C3’, C3’-C2’, and C3’-C8’ bond distances and C3-C10-C3’, C2-C3-C9 and C10-C3’-C8’ bond angles and their data is presented in Table 3 and 4. The substitution of groups at C10 position of the bis-indole nucleus causes significant change in the value of bond distances in rings A and A’. i) The bond distance C10-C3 (sp3-sp2) lies in the range 1.480-1.532 Å [Average value of 1.506 Å] and the bond distance C10-C3’ (sp3-sp2) lies in the range 1.457-1.528 Å [Average value of 1.510 Å]. Whereas the bond distance C3-C2 (sp2-sp2) lies in the range 1.343-1.382 Å [average value of 1.361 Å] and the bond distance C3’-C2’ (sp2-sp2) lies in the range 1.351-1.442 Å [Average value of 1.365 Å]. Moreover, the bond distance C3-C9 (sp2-sp2) lies in the range 1.365-1.464 Å [Average value of 1.436 Å]. The bond distance C3’-C8’ (sp2-sp2) lies in the range 1.364- 1.480 Å [Average value of 1.436 Å]. ii) The substitution of a group at C10 (sp3) position also causes a significant change in the value of bond angle C3-C10- C3’. The bond angle C3-C10-C3’ in molecules with a substituent group at the C10 (sp3) position varies from 108.60 to 114.65° [Average value of 112.81°]. The bond angle C10-C3-C2 and C10- C3’-C2’ in molecules with a substituent group at the C10 (sp3) position varies from 113.18 to 129.36° [Average value of 126.82°] and from 124.58 to 131.09° [Average value of 127.45°]. The bond angle C2-C3-C9 and C2’-C3’-C8’ in molecules with a substituent group at the C10 (sp3) position varies from 104.26 to 108.30° [Average value of 106.24°] and from 103.99 to 107.01° [Average value of 106.20°]. The bond angle C10-C3- C9 and C10-C3’-C8’ in molecules with a substituent group at the C10 (sp3) position varies from 123.52 to 131.37° [Average value of 126.55°] and from 122.48 to 129.00° [Average value of 126.55°]. The deviation of these bond distances and angles may be due to the effect of some functional group located at C10 (sp3) position which invariably is involved in intra-/inter-molecular interactions. 496 Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 3. Selected bond distances (Å) for molecules M1-41 *. Molecule [C10-C3] [C10-C3’] [C3-C2] [C3’-C2’] [C3-C9] [C3’-C8’] sp3-sp2 sp3-sp2 sp2-sp2 sp2-sp2 sp2-sp2 sp2-sp2 M1 1.515 1.514 1.368 1.364 1.439 1.442 M2A 1.505 1.503 1.342 1.386 1.464 1.480 M2B 1.503 1.505 1.353 1.360 1.429 1.440 M3 1.506 1.527 1.365 1.363 1.365 1.438 M4 1.521 1.520 1.382 1.383 1.449 1.440 M5 1.494 1.528 1.362 1.359 1.431 1.442 M6 1.510 1.517 1.365 1.371 1.431 1.440 M7 1.502 1.503 1.358 1.356 1.437 1.435 M8 1.493 1.513 1.356 1.358 1.451 1.440 M9 1.510 1.513 1.356 1.369 1.442 1.440 M10 1.509 1.508 1.357 1.357 1.432 1.432 M11 1.522 1.507 1.343 1.442 1.439 1.442 M12 1.472 1.457 1.370 1.365 1.440 1.449 M13 1.480 1.472 1.374 1.376 1.438 1.438 M14 1.511 1.511 1.355 1.367 1.433 1.436 M15 1.505 1.507 1.357 1.354 1.424 1.428 M16 1.515 1.519 1.362 1.358 1.433 1.437 M17 1.514 1.512 1.370 1.361 1.432 1.429 M18 1.515 1.507 1.365 1.357 1.438 1.433 M19 1.532 1.513 1.371 1.349 1.416 1.432 M20 1.516 1.511 1.363 1.359 1.439 1.441 M21Ⅰ 1.516 1.512 1.379 1.357 1.436 1.459 M21ⅠI 1.517 1.540 1.359 1.362 1.455 1.444 M22 1.519 1.513 1.379 1.385 1.443 1.434 M23 1.509 1.528 1.358 1.373 1.435 1.431 M24 1.505 1.506 1.361 1.356 1.433 1.429 M25 1.516 1.513 1.360 1.364 1.435 1.435 M26 1.516 1.510 1.359 1.364 1.443 1.435 M27 1.519 1.505 1.370 1.363 1.432 1.440 M28 1.509 1.502 1.365 1.354 1.432 1.431 M29 1.512 1.504 1.353 1.365 1.442 1.439 M30 1.507 1.511 1.354 1.359 1.435 1.438 M31 1.516 1.510 1.365 1.374 1.450 1.434 M32 1.510 1.512 1.362 1.359 1.436 1.428 M33A 1.349 1.513 1.349 1.359 1.434 1.426 M33B 1.514 1.509 1.358 1.361 1.435 1.441 M33C 1.506 1.508 1.354 1.362 1.434 1.430 M34 1.511 1.505 1.353 1.357 1.434 1.439 M35 1.527 1.510 1.364 1.355 1.452 1.434 M36 1.518 1.519 1.375 1.372 1.425 1.433 M37 1.508 1.511 1.360 1.364 1.443 1.364 M38 1.498 1.514 1.350 1.356 1.435 1.439 M39A 1.497 1.514 1.369 1.351 1.432 1.424 M39B 1.511 1.504 1.359 1.362 1.433 1.436 M40 1.521 1.509 1.366 1.372 1.440 1.432 Average 1.506 1.510 1.361 1.365 1.436 1.436 * A, B, and C refers to polymorphic forms; Ⅰ and Ⅱ refers to crystallographic independent molecules. 3.3. Biological activity predictions The biological-activity relationship as presented in Table 5, the computation of various activities of bis-indole derivatives by using PASS software possesses 5-hydroxytryptamine release stimulant, Aspulvinonedimethylallyl transferase inhibitor, Preneoplastic conditions treatment, Endothelial growth factor antagonist and Lyase inhibitor activities. Majority of the iden- tified molecules exhibit greater probability for 5-hydroxy- tryptamine release stimulants except [M12]. A comparison of possible activities shows that the molecules M1, M3, M8, M13, M14, M15, M16, M18, M20, M21, M25, M26, M29, M33, M34, M37, M38, and M39 exhibit very high value of positive 5- hydroxytryptamine release stimulant activity while other molecules show high or low/neutral activity. The identified molecules exhibit high biological activity for Aspulvinone dimethylallyl transferase inhibitor except (M7, M9). The probability of very high Aspulvinonedimethylallyl transferase inhibitor activity lies in molecules viz. M2, M13, M25, M27, and M40, whereas the other molecules exhibit almost neutral or low values. Similarly, the most of the identified molecules exhibit greater probability for Preneoplastic conditions treatment except (M5, M7), where molecules M1, M24, M29, M33, and M34 have very high activity. The identified molecules exhibit high biological activity for Endothelial growth factor antagonists except (M38, M40). The Pa > Pi value for Endothelial growth factor antagonist activity shows that it has high positivity value only for molecule M2. Whereas positive Lyase inhibitor activity has been shown by almost all molecule except (M5, M7, M12). It is observed that Lyase inhibitor activity is very high for molecules M1, M8, M9, M10, M11, M15, M16, M18, M21, M24, M26, M33, M34, M35, and M39. 3.4. Molecular packing interactions Directionality of intermolecular hydrogen bonding plays an important role in molecular packing. And d-θ and D-θ scatter plots have a significant role in analysing the directionality of hydrogen bonds. The plots contain all contacts found in molecule (1-41) with d < 2.85 Å and D < 3.6209 Å at any occurring angle (θ). The d-θ scatter plots have been made for intermolecular hydrogen bonds as shown in Figure 2a and b, respectively. i) From the pie chart, the frequency of occurrence of N- H···O, C-H···O, C-H···F, N-H···N, N-H···S, and C-H···N inter- molecular hydrogen bonds is 67.3, 17.3, 5.7, 5.7, 1.9 and 1.9%, respectively, and are presented in Figure 3. N-H···O is the most preferred intermolecular interaction in bis-indole class. ii) In case of N-H···O hydrogen bond, the density of spots for d(H···A) = 1.95-2.15 Å; D(X···A) = 2.80-3.00 Å and θ (X–H···A) = 145-165°. Most of the N-H···O contacts belongs to the category of strong hydrogen bond. Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 497 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 4. Selected bond angles (°) for molecules M1-41 *. Molecule [C3-C10-C3’] [C2-C3-C9] [C2’-C3’-C8’a] [C10-C3-C2] [C10-C3’-C2’] [C10-C3-C9] [C10-C3’-C8’] C10 (sp3) C1 (sp2) C1’ (sp2) C1 (sp3) C1’ (sp3) C1 (sp3) C1’ (sp3) M1 114.10 105.94 106.14 127.01 129.18 126.76 124.46 M2A 112.26 107.70 103.99 113.18 129.57 123.84 126.45 M2B 112.49 106.26 106.16 129.04 127.64 124.70 126.20 M3 113.24 106.46 106.81 127.27 127.61 127.04 127.61 M4 112.69 105.55 106.25 123.08 125.38 131.37 128.27 M5 112.87 105.89 106.92 125.90 126.54 128.18 126.34 M6 114.49 106.04 106.16 127.43 125.57 126.22 128.00 M7 113.60 105.91 106.14 128.48 124.97 125.51 124.97 M8 112.85 105.73 105.88 127.21 125.33 125.33 127.21 M9 112.89 107.06 106.51 126.46 125.61 125.83 127.68 M10 112.17 106.44 106.44 127.27 127.29 126.25 126.24 M11 110.89 107.37 105.63 127.10 128.21 125.44 126.00 M12 116.84 105.76 106.12 125.39 125.29 128.73 128.49 M13 120.10 106.75 106.42 128.31 128.49 124.91 125.08 M14 113.08 106.75 106.42 128.78 128.68 124.84 125.19 M15 113.07 106.22 106.65 127.70 127.69 126.08 125.60 M16 110.54 106.32 106.60 126.11 125.49 127.52 127.87 M17 113.21 106.43 106.40 127.03 127.85 126.42 125.64 M18 113.82 105.93 106.34 126.82 129.33 127.16 124.32 M19 112.41 106.33 106.72 125.73 128.24 127.50 125.41 M20 112.29 106.62 106.14 123.37 127.32 129.90 126.30 M21Ⅰ 111.02 105.84 105.62 125.68 128.29 128.47 125.74 M21Ⅱ 108.60 104.26 106.90 126.80 126.17 128.52 126.82 M22 113.12 105.94 105.78 123.54 125.89 130.52 128.13 M23 110.58 106.48 106.76 124.20 124.58 129.27 128.12 M24 113.07 105.79 106.27 128.93 128.72 125.20 124.96 M25 112.58 106.28 105.82 128.10 126.36 125.61 127.82 M26 113.35 105.94 105.76 129.31 129.03 124.73 125.21 M27 113.10 106.11 105.75 126.66 128.08 127.08 126.12 M28 112.30 105.67 106.24 127.55 127.79 126.76 125.95 M29 112.52 106.27 105.63 127.73 129.87 126.00 124.37 M30 114.50 105.58 106.00 129.14 128.96 124.19 124.39 M31 112.43 106.66 106.27 124.00 124.66 129.30 129.00 M32 112.23 106.28 106.55 127.56 128.08 126.16 125.36 M33A 111.50 105.80 106.05 128.39 128.17 125.79 125.77 M33B 111.31 106.04 106.75 129.18 127.77 125.77 125.48 M33C 111.24 106.54 106.14 128.03 127.75 125.42 126.10 M34 112.71 106.17 105.75 128.12 128.21 125.35 126.02 M35 113.18 108.30 105.50 126.17 128.85 125.31 125.52 M36 113.75 107.51 106.43 128.94 131.09 123.52 122.48 M37 111.58 106.08 106.33 128.64 128.07 125.27 125.60 M38 114.65 106.26 106.62 128.53 125.52 125.21 127.84 M39A 112.53 104.75 106.25 129.36 127.33 125.87 126.29 M39B 112.33 106.13 105.91 127.28 128.82 126.46 125.21 M40 112.38 106.90 107.01 126.61 125.84 129.49 127.14 Average 112.81 106.24 106.20 126.82 127.45 126.55 126.55 * A, B, and C refers to polymorphic forms; Ⅰ and Ⅱ refers to crystallographic independent molecules. (a) (b) Figure 2. (a) d-θ scatter plot for intermolecular N-H···O, C-H···O, C-H···F, N-H···N, N-H···S and C-H···N; (b) D-θ scatter plot for intermolecular N-H···O, C-H···O, C- H···F, N-H···N, N-H···S and C-H···N. iii) Density spots of C-H···O type of hydrogen bonds is maximum for range (d(H···A) = 2.52-2.58 Å; D(X···A) = 3.15- 3.35 Å and θ(X–H···A) = 125-135°). Most of the C-H···O contacts belongs to the category of weak hydrogen bond. iv) The range of d(H···A), D(X-H···A) and θ(X–H···A) for all the obtained data of intermolecular hydrogen interactions of the type N-H···O, C-H···O, C-H···F, N-H···N, N-H···S and C-H···N lies between 1.94-2.85 Å, 2.7669-3.6209 Å and 123-178°, respe- ctively. Table 7 presents all the range for d(H···A), D(X···A) and Θ(X- H···A) of various types of intermolecular bonds in the identified molecules. 498 Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 5. Pa and Pi values for the molecule 1-41 *. Molecule 5-Hydroxytryptamine release stimulant Aspulvinonedimethylallyl transferase inhibitor Preneoplastic conditions treatment Endothelial growth factor antagonist Lyase inhibitor Pa > Pi Pa > Pi Pa > Pi Pa > Pi Pa > Pi M1 0.878 > 0.007 0.688 > 0.068 0.816 > 0.003 0.433 > 0.017 0.754 > 0.015 M2A 0.639 > 0.034 0.751 > 0.048 0.599 > 0.024 0.603 > 0.005 0.611 > 0.040 M2B 0.639 > 0.034 0.751 > 0.048 0.599 > 0.024 0.603 > 0.005 0.611 > 0.040 M3 0.722 > 0.023 0.524 > 0.127 0.520 > 0.046 0.367 > 0.029 0.647 > 0.033 M4 0.639 > 0.034 0.751 > 0.048 0.599 > 0.024 0.603 > 0.005 0.611 > 0.040 M5 0.242 > 0.148 0.311 > 0.260 - 0.178 > 0.159 - M6 0.640 > 0.034 0.311 > 0.260 0.326 > 0.148 0.294 > 0.056 0.366 > 0.112 M7 0.242 > 0.148 - - 0.178 > 0.159 - M8 0.719 > 0.023 0.364 > 0.217 0.623 > 0.019 0.394 > 0.023 0.776 > 0.012 M9 0.228 > 0.158 - 0.607 > 0.023 0.252 > 0.082 0.753 > 0.015 M10 0.742 > 0.020 0.580 > 0.105 0.667 > 0.012 0.471 > 0.012 0.741 > 0.017 M11 0.772 > 0.017 0.533 > 0.123 0.614 > 0.021 0.483 > 0.011 0.725 > 0.019 M12 - 0.558 > 0.113 0.256 > 0.217 0.305 > 0.047 - M13 0.864 > 0.008 0.832 > 0.025 0.550 > 0.037 0.402 > 0.022 0.596 > 0.043 M14 0.864 > 0.008 0.487 > 0.143 0.562 > 0.033 0.386 > 0.025 0.598 > 0.043 M15 0.834 > 0.011 0.613 > 0.093 0.595 > 0.025 0.371 > 0.028 0.717 > 0.020 M16 0.817 > 0.013 0.621 > 0.090 0.655 > 0.014 0.562 > 0.007 0.739 > 0.017 M17 0.618 > 0.036 0.446 > 0.164 0.701 > 0.009 0.482 > 0.014 0.644 > 0.033 M18 0.779 > 0.016 0.645 > 0.082 0.647 > 0.015 0.377 > 0.027 0.764 > 0.014 M19 0.483 > 0.055 0.390 > 0.198 0.330 > 0.145 0.274 > 0.067 0.282 > 0.175 M20 0.722 > 0.023 0.524 > 0.127 0.520 > 0.046 0.367 > 0.029 0.647 > 0.033 M21 0.883 > 0.006 0.668 > 0.074 0.676 > 0.011 0.389 > 0.024 0.803 > 0.009 M22 0.301 > 0.111 0.410 > 0.185 0.456 > 0.071 0.307 > 0.050 0.292 > 0.165 M23 0.326 > 0.100 0.489 > 0.143 0.696 > 0.009 0.271 > 0.069 0.723 > 0.019 M24 0.893 > 0.005 0.730 > 0.054 0.736 > 0.006 0.478 > 0.012 0.794 > 0.010 M25 0.748 > 0.020 0.743 > 0.050 0.478 > 0.061 0.255 > 0.080 0.423 > 0.089 M26 0.867 > 0.008 0.584 > 0.103 0.639 > 0.017 0.370 > 0.029 0.823 > 0.007 M27 0.578 > 0.041 0.716 > 0.058 0.472 > 0.064 0.238 > 0.093 0.424 > 0.088 M28 0.497 > 0.052 0.585 > 0.103 0.401 > 0.098 0.213 > 0.116 0.435 > 0.084 M29 0.468 > 0.057 0.444 > 0.165 0.800 > 0.004 0.334 > 0.039 0.818 > 0.008 M30 0.766 > 0.018 0.585 > 0.103 0.662 > 0.013 0.337 > 0.038 0.730 > 0.018 M31 0.307 > 0.108 0.625 > 0.089 0.614 > 0.021 0.349 > 0.034 0.490 > 0.068 M32 0.692 > 0.027 0.534 > 0.123 0.737 > 0.005 0.526 > 0.009 0.661 > 0.030 M33A 0.863 > 0.008 0.660 > 0.077 0.703 > 0.008 0.411 > 0.020 0.785 > 0.011 M33B 0.863 > 0.008 0.660 > 0.077 0.703 > 0.008 0.411 > 0.020 0.758 > 0.011 M33C 0.863 > 0.008 0.660 > 0.077 0.703 > 0.008 0.411 > 0.020 0.785 > 0.011 M34 0.894 > 0.005 0.697 > 0.065 0.724 > 0.006 0.471 > 0.012 0.815 > 0.008 M35 0.665 > 0.030 0.446 > 0.164 0.648 > 0.015 0.362 > 0.031 0.849 > 0.005 M36 0.589 > 0.040 0.660 > 0.077 0.519 > 0.046 0.558 > 0.007 0.603 > 0.041 M37 0.816 > 0.013 0.446 > 0.164 0.555 > 0.035 0.363 > 0.031 0.603 > 0.036 M38 0.761 > 0.018 0.500 > 0.137 0.411 > 0.092 - 0.315 > 0.145 M39A 0.886 > 0.006 0.667 > 0.074 0.696 > 0.009 0.443 > 0.015 0.795 > 0.010 M39B 0.886 > 0.006 0.667 > 0.074 0.696 > 0.009 0.443 > 0.015 0.795 > 0.010 M40 0.669 > 0.030 0.743 > 0.050 0.397 > 0.100 - 0.352 > 0.120 * “-“ indicates the absence of a particular type of biological activity. Table 6. Geometry of N-H···O, C-H···O, C-H···F, N-H···N, N-H···S and C-H···N inter-molecular interactions. Molecule [Number of Donors and Accepters] X-H···A H···A (Å) X···A (Å) ∠ X-H···A (°) M1, TAXTAQ, Donors = 3 Acceptors = 2 N1-H1P···O1 C5-H5···O1 C25-H25A···O2 2.24 2.52 2.55 3.0035 3.3729 3.4640 148 153 159 M2A, TEVTIY, Donors = 1 Acceptors = 1 N2-H2A···O1 2.35 2.9730 129 M2B, TEVTIY01, Donors = 2 Acceptors = 2 N3-H3···O4 N4-H4···O2 2.36 2.38 2.9793 2.9872 129 128 M3, DEFMEH, Donors = 3 Acceptors = 2 N1-H1···O2 N2-H2···O1 N3-H3···O1 1.98 2.12 2.27 2.8190 2.9659 3.0270 159 161 145 M4, DOPZIT, Donors = 2 Acceptors = 2 N1-H1A···O3 N2-H2A···O1 2.08 2.04 2.9229 2.8621 168 159 M5, EHINAM, Donors = 1 Acceptors = 1 N2-H2A···O1 2.00 2.7966 154 M6, EMIGUE, Donors = 5 Acceptors = 4 N1-H1···S2 N1-H1···O2 N11-H11···O1 N21-H21···O1 C31-H20C···O2 C32-H30C···F10 2.85 2.00 2.00 2.09 2.59 2.54 3.6209 2.8201 2.8541 2.8453 3.5210 3.4735 150 159 169 146 165 165 M7, EVAKES, Donors = 2 Acceptors = 1 N2-H2A···N1 N3-H3A···N1 2.34 2.22 3.2063 3.0843 160 178 M8, GIHDUY, Donors = 1 Acceptors = 1 N2-H2···N3 2.28 3.0389 147 M9, GUCJEY, Donors = 3 Acceptors = 2 N1-H1···O22 N10-H10···O101 N23-H23···O22 2.21 1.94 2.14 3.0166 2.7669 2.9130 157 160 149 M12, HOYPAN, Donors = 1 Acceptors = 1 C11-H11···O2 2.53 3.2032 129 M14, KEQREE, Donors = 2; Acceptors = 2 N2-H2A···O1 C3-H3A···F 2.16 2.51 2.9464 3.2630 152 138 M15, KIFMES, Donors = 1; Acceptors = 1 N1-H1···O2 2.46 3.1851 144 M16, LANFIS, Donors = 2; Acceptors = 2 N1-H1···O2 N2-H2···O1 2.25 2.10 3.0702 2.9158 159 158 Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 499 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 Table 6. Continued. Molecule [Number of Donors and Accepters] X-H···A H···A (Å) X···A (Å) ∠ X-H···A (°) M17, LAWGEY, Donors = 1; Acceptors = 1 N1-H1···O1 2.12 2.9122 152 M18, LOKKON, Donors = 2; Acceptors = 2 N1-H1A···O1A N1-H1A···O1 N2-H2B···O1A N2-H2B···O1 2.07 2.16 2.20 2.11 2.9016 3.0043 2.9610 2.9135 162 165 147 154 M19, MAVCUI, Donors = 1; Acceptors = 1 N1-H1···O1 2.08 2.9123 162 M20, MEDJEK, Donors = 2; Acceptors = 2 N1-H1A···O4 N2-H2A···O2 2.07 2.07 2.9029 2.8917 162 159 M21, NUQGAJ, Donors = 2; Acceptors = 2 N1-H1A···O4 N2-H2A···O2 2.07 2.07 2.9029 2.8917 162 159 M23, OCESAS, Donors = 1; Acceptors = 1 N1-H1A···O2 2.09 2.9034 158 M28, PEMLUP, Donors = 2; Acceptors = 2 N2-H2A···O1 C1-H1D···O4 2.12 2.47 2.8995 3.2106 151 134 M29, PUZCAQ, Donors = 2; Acceptors = 1 N3-H9···O1 C13-H11···O1 2.42 2.50 3.1318 3.2348 136 130 M30, QINXAO, Donors = 2; Acceptors = 4 N2-H2A···O2 C11-H11A···O3 C11-H11B···N1 C11-H11C···O4 2.02 2.60 2.61 2.53 2.8703 3.2207 3.4425 3.3334 169 123 145 124 M31, SESMIN, Donors = 1; Acceptors = 1 N1-H1A···O2 2.30 2.9364 131 M35, UKAYIQ, Donors = 1; Acceptors = 1 C20-H14···O1 2.59 3.3991 146 M36, UNOPOE, Donors = 1; Acceptors = 1 C5-H5···F26 2.51 3.3849 157 Table 7. Range for d (H···A), D (X···A) and Θ (X-H···A) of various types of intermolecular bonds. Type of hydrogen bond d(H···A) range (Å) D (X···A) range (Å) Θ (X-H···A) range (°) N-H···O 1.94-2.46 2.7669-3.1851 128-169 C-H···O 2.47-2.60 3.2032-3.521 123-165 C-H···F 2.51-2.54 3.2630-3.4735 138-165 N-H···N 2.22-2.34 3.0389-3.2063 147-178 N-H···S 2.85 * 3.6209 * 150 * C-H···N 2.61 * 3.4425 * 145* * Indicates only one bond of this type is present. Figure 3. Relative frequency of occurrence (%) for various types of intermolecular hydrogen bonding. Table 8. Geometrical parameters for very strong, strong and weak hydrogen bonds. Property Very strong Strong Weak Present work D(H···A), Å 1.2-1.5 1.5-2.2 2.0-3.0 1.94-2.85 D(X···A), Å 2.0-2.5 2.5-3.2 3.2-4.0 2.77-3.62 Θ(X-H···A), ° 175-180 130-180 90-180 123-178 On the basis of Table 8 which presents a comparison of geometrical parameters for strength of hydrogen bonds [57], the hydrogen bonding strength of the identified molecules is of strong to weak nature. Among the identified BIMs, all intermolecular bifurcated hydrogen bonding is due to donor N atom and acceptor O and N atoms. The bifurcated hydrogen bonding for donor N atoms are observed in molecule (M6 and M18) and bifurcated hydrogen bonding for accepter O and N atoms are observed in a molecule M1, M3, M6, M7, M9, M18 and M31, respectively. In molecules M1, M3, M6, M7, M9, M18, and M31, the bifurcated hydrogen bonds O and N atoms are involved in hydrogen bonds [N1- H1P···O1/C5-H5···O1, N2-H2···O1/N3-H3···O1, N1-H1···O2/ C31-H20C···O2, N11-H11···O1/N21-H21···O1, N2-H2A···N1/ N3-H3A···N1, N1-H1···O22/N23-H23···O22, N1-H1A···O1A/N2- H2B···O1A and N3-H9···O1/C13-H11···O1]. The molecule M6 has three bifurcated hydrogen bonding, due to the presence of donor N atom and acceptor O atom. In the present study, majority of bifurcated hydrogen bonds are due to O acceptor site. The bifurcated hydrogen bond donor forms intermolecular bond [N1-H1···S2 and N1-H1···O2] with bifurcated angle 309° in M6. 4. Conclusion In the present work, the crystallography comparison of bis- indole derivatives has been done along with their biological activity prediction and molecular packing interaction. The biological-activity are characterized by Pa and Pi values which depict that majority of the molecules undertaken for present study have high value of 5-hydroxytryptamine release stimu- lant inhibitor activity. The analysis of hydrogen bonding is quite interesting due to the nature of substitution at position C10 of bis-indole ring system. Bis-indole derivatives have mostly crystallized in monoclinic crystal system followed by triclinic and orthorhombic crystal system. The deviation of bond distance (C10-C3, C3-C2, C3-C9, C10-C3’, C3’-C2’, and C3’-C8’) and bond angle (C3-C10-C3’, C2-C3-C9 and C10-C3’-C8’) is due 500 Sharma et al. / European Journal of Chemistry 12 (4) (2021) 493-501 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.4.493-501.2145 to the involvement of variety of substituent’s at position C10 in hydrogen bonding interactions. On the basis of hydrogen bonding interaction data, it may be concluded that almost all the N-H···O intermolecular interaction belongs to the category of strong hydrogen bonding, whereas majority of C-H···O and C- H···F contacts belongs to weak interaction. The molecules M1, M3, M6, M7, M9, M17 and M30 depict the phenomenon of bifurcated hydrogen bonding and most of these bifurcated hydrogen bonds are due to the O acceptor atom. Most of the H- bonds are based on N-H···O. This show that due to substitution at position C10 of bis-indole ring N donor atom dominates over other atoms in intermolecular hydrogen bond formation. The design of new molecules with desired properties is the future intention of chemists/crystallographers, which requires the clear understanding of intermolecular interactions in crystal packing. Thus, understanding of intermolecular interactions in- depth becomes vital. Acknowledgements Vivek Kumar Gupta is thankful to University of Jammu, Jammu, India, for financial support under Rashtriya Uchchatar Shiksha Abhiyan (RUSA) 2.0 Project (Ref. No: RUSA/JU/2/ 2019-20/111/3588-3636). Supporting information The data of chemical structure of molecule 1-41 data can be obtained free of charge via https://www.ccdc.cam.ac.uk/ structures/, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are not available from the author. CRediT authorship contribution statement Conceptualization: Varun Sharma; Methodology: Varun Sharma; Software: Varun Sharma; Validation: Goutam Brahmachari; Formal Analysis: Goutam Brahmachari; Investigation: Goutam Brahmachari; Resources: Vivek Kumar Gupta; Data Curation: Vivek Kumar Gupta; Writing - Original Draft: Varun Sharma; Writing - Review and Editing: Vivek Kumar Gupta; Visualization: Vivek Kumar Gupta; Funding acquisition: Vivek Kumar Gupta; Supervision: Vivek Kumar Gupta; Project Administration: Vivek Kumar Gupta. ORCID Varun Sharma https://orcid.org/0000-0003-2866-8638 Goutam Brahmachari https://orcid.org/0000-0001-9925-6281 Vivek Kumar Gupta https://orcid.org/0000-0003-2471-5943 References [1]. Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer Lett. 2008, 269 (2), 326–338. [2]. Chu, X.-Q.; Zi, Y.; Lu, X.-M.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2014, 70 (2), 232–238. [3]. Wong, G. Y.; Bradlow, L.; Sepkovic, D.; Mehl, S.; Mailman, J.; Osborne, M. P. J. Cell. Biochem. 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The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Methodology 2.1. Crystallographic comparison 2.2. Biological activity predictions 2.3. Molecular packing interaction analysis 3. Discussion 3.1. Comparative crystallographic analysis 3.2. Bond distance and angles 3.3. Biological activity predictions 3.4. Molecular packing interactions 4. Conclusion Acknowledgements Supporting information Disclosure statement CRediT authorship contribution statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: