Crystal structure determination and Hirshfeld surface analysis of N-acetyl-N-3-meth-oxy-phenyl and N-(2,5-di-meth-oxy-phen-yl)-N-phenyl-sulfonyl derivatives of N-[1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine.

Two new [1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine derivatives, namely, N-(3-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}acetamide, C24H22N2O4S, (I), and N-(2,5-di-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}benzene-sulfonamide, C29H26N2O6S2, (II), reveal a nearly orthogonal orientation of their indole ring systems and sulfonyl-bound phenyl rings. The sulfonyl moieties adopt the anti-periplanar conformation. For both compounds, the crystal packing is dominated by C-H⋯O bonding [C⋯O = 3.312 (4)-3.788 (8) Å], with the structure of II exhibiting a larger number, but weaker bonds of this type. Slipped π-π inter-actions of anti-parallel indole systems are specific for I, whereas the structure of II delivers two kinds of C-H⋯π inter-actions at both axial sides of the indole moiety. These findings agree with the results of Hirshfeld surface analysis. The primary contributions to the surface areas are associated with the contacts involving H atoms. Although II manifests a larger fraction of the O⋯H/H⋯O contacts (25.8 versus 22.4%), most of them are relatively distal and agree with the corresponding van der Waals separations.

Synthesis of Indolo[2,3/3,2-c]quinoline through Complementary PIDA/BF3·OEt2 as Well as Pd(0)-Mediated Intramolecular Cyclization of Isomeric N-((Aryl)-N-(phenylsulfonyl)indolyl)methylbenzenesulfonamides.

Herein, a straightforward facile synthesis of indolo[2,3-c]quinoline analogues was reported from 2-arylamino(phenylsulfonyl)methylindoles involving PIDA/BF3·OEt2-mediated intramolecular dehydrogenative coupling (IDC) as a key step. Even though isomeric 3-arylamino(phenylsulfonyl)methylindoles, upon interaction with PIDA/BF3·OEt2, led to complications, synthesis of the indolo[3,2-c]quinoline framework could be easily achieved from N-(2-iodoaryl)-N-indolylmethylbenzenesulfonamide by employing a Pd(0)-mediated intramolecular cyclization reaction. Under identical conditions, synthesis of indolo[2,3-c]quinolines was also accomplished from the respective N-(2-iodoaryl)-N-indolylmethylbenzenesulfonamides. The SRB assay of fluorine-bound indoloquinolines displayed nanomolar-level cytotoxicity against a nonsmall lung cancer cell line, NCI-H460.

Synthesis of α-, ß-, and γ-Carbolines via Intramolecular Cyclization of Azidomethyl(indolyl)acrylates Involving PIFA-BF3·OEt2/DBU-Mediated Cyclization as well as Thermolysis Approaches.

In this study, we present our findings on the synthesis of α-, ß-, γ-carbolines via PIFA/BF3·OEt2-mediated intramolecular cyclization of isomeric azidomethyl(indolyl)acrylates. Alternately, 1,5,7-triazabicyclo[4.4.0]dec-5-ene/1,8-diazabicyclo(5.4.0)undec-7-ene (TBD/DBU)-mediated Michael addition followed by intramolecular cyclization of isomeric 2/3-(azidomethyl)indol-3/2-yl)acrylates also furnished the respective ß- and γ-carboline derivatives. Unexpectedly, the thermolysis of 2-(azidomethyl)-3-(indol-3-yl)acrylates led to the formation of ethyl 5-(2-(phenylsulfonamido)aryl)nicotinates along with γ-carbolines, via nitrene insertion followed by rearrangement and cyclization. The isomeric 2-(azidomethyl)-3-(indol-2-yl)acrylate upon thermolysis led to the expected δ-carboline. Thermal intramolecular nitrene insertion reaction could also be extended for accessing pyrido benzothiophene, pyrido thiophene, and quinoline.

The crystal structures and Hirshfeld surface analysis of three new bromo-substituted 3-methyl-1-(phenyl-sulfon-yl)-1H-indole derivatives.

Three new 1H-indole derivatives, namely, 2-(bromo-meth-yl)-3-methyl-1-(phenyl-sulfon-yl)-1H-indole, C16H14BrNO2S, (I), 2-[(E)-2-(2-bromo-5-meth-oxy-phen-yl)ethen-yl]-3-methyl-1-(phenyl-sulfon-yl)-1H-indole, C24H20BrNO3S, (II), and 2-[(E)-2-(2-bromo-phen-yl)ethen-yl]-3-methyl-1-(phenyl-sulfon-yl)-1H-indole, C23H18BrNO2S, (III), exhibit nearly orthogonal orientations of their indole ring systems and sulfonyl-bound phenyl rings. Such conformations are favourable for inter-molecular bonding involving sets of slipped π-π inter-actions between the indole systems and mutual C-H⋯π hydrogen bonds, with the generation of two-dimensional monoperiodic patterns. The latter are found in all three structures, in the form of supra-molecular columns with every pair of successive mol-ecules related by inversion. The crystal packing of the compounds is additionally stabilized by weaker slipped π-π inter-actions between the outer phenyl rings (in II and III) and by weak C-H⋯O, C-H⋯Br and C-H⋯π hydrogen bonds. The structural significance of the different kinds of inter-actions agree with the results of a Hirshfeld surface analysis and the calculated inter-action energies. In particular, the largest inter-action energies (up to -60.8 kJ mol-1) are associated with pairing of anti-parallel indole systems, while the energetics of weak hydrogen bonds and phenyl π-π inter-actions are comparable and account for 13-34 kJ mol-1.

Synthesis of Cytotoxic Quino[4,3-b]carbazole Frameworks through an Intramolecular Diels-Alder Reaction.

An intramolecular Diels-Alder reaction of positionally isomeric indole-2/3-phenylvinyl-N-alkynylated (N-phenylsulfonyl)amines has been successfully exploited for the synthesis of quino[4,3-b]carbazole and its analogues. This reaction proceeds through a [4 + 2] cycloaddition followed by elimination and deprotection of phenylsulfonyl units to afford the quinocarbazoles in moderate to good yields. The reaction features a broad substrate scope and remarkable functional group forbearance. A preliminary in vitro cytotoxicity evaluation of representative quino[4,3-b]carbazoles was performed against NCI-H460 human cancer cell culture. Among the quino[4,3-b]carbazoles evaluated, five of the fluorine-containing quinocarbazoles displayed nano molar range (0.8-2.0 nm) GI50 values. The UV-vis and fluorescence spectral studies of representative quinocarbazoles were also performed. Like ellipticine, four of the quinocarbazoles displayed dual emissions confirming the existence of p-quinonoid like tautomeric forms in a polar protic solvent.

Crystal structure and Hirshfeld surface analysis of 3-(bromo-meth-yl)-2-[1,2-di-bromo-2-(6-nitro-benzo[d][1,3]dioxol-5-yl)eth-yl]-1-(phenyl-sulfon-yl)-1H-indole chloro-form 0.585-solvate.

The title indole derivative, C24H17Br3N2O6S, crystallizes with a partial occupancy [0.585 (4)] CHCl3 solvent mol-ecule. The dihedral angles between the indole ring system and pendant nitro-benzodioxolane rings system and phenyl-sulfonyl ring are 4.81 (14) and 72.24 (19)°, respectively. In the crystal, the indole mol-ecules are linked to each other and to the chloro-form mol-ecule by weak C-H⋯O, C-H⋯Cl, C-H⋯π, C-Br⋯π and C-Cl⋯π and aromatic π-π stacking inter-actions. A Hirshfeld surface analysis was carried out and the inter-molecular contacts with the most significant contributions are H⋯O/O⋯H (24.3%), H⋯H (18.4%), Br⋯H/H⋯Br (16.8%) and C⋯H/H⋯C (8.4%).

Crystal-structure determination and Hirshfeld surface analysis of two new thio-phene derivatives: (E)-N-{2-[2-(benzo[b]thio-phen-2-yl)ethen-yl]-5-fluoro-phen-yl}benzene-sulfonamide and (E)-N-{2-[2-(benzo[b]thio-phen-2-yl)ethen-yl]-5-fluoro-phen-yl}-N-(but-2-yn-1-yl)benzene-sulfonamide.

In the title compounds, C22H16FNO2S2 (I) and C26H20FNO2S2 (II), the benzo-thio-phene rings are essentially planar with maximum deviations of 0.009 (1) and 0.001 (1) Šfor the carbon and sulfur atom in compounds I and II, respectively. In I, the thio-phene ring system is almost orthogonal to the phenyl ring attached to the sulfonyl group, with a dihedral angle of 77.7 (1)°. In compound I, the mol-ecular structure is stabilized by weak C-H⋯O intra-molecular inter-actions formed by the sulfone oxygen atoms, which generate two S(5) ring motifs. In the crystal of I, N-H⋯O hydrogen bonds link the mol-ecules into R 2 2(8) rings, which are connected into a C(10) chain via C-H⋯F hydrogen bonds. Inter-molecular C-H⋯π inter-actions are also observed. In compound II, the mol-ecules are linked via C-H⋯O and C-H⋯F hydrogen bonding, generating infinite C(11) and C(13) chains running parallel to [010].

The synthesis, crystal structure and Hirshfeld surface analysis of the thio-phene derivatives 5-(phenyl-sulfon-yl)-5,6-di-hydro-benzo[4,5]thieno[3,2-j]phenanthridine and (E)-N-{2-[2-(benzo[b]thiophen-2-yl)ethenyl]phen-yl}-N-(prop-2-yn-1-yl)benzene-sulfonamide.

In both of the title compounds, C26H19NO2S2, (I), and C25H19NO2S2, (II), the benzo-thio-phene rings are essentially planar with maximum deviations of 0.026 (1) and -0.016 (1) Šfor the carbon and sulfur atoms in compounds (I) and (II), respectively. In (I), the thio-phene ring system is almost orthogonal to the phenyl ring attached to the sulfonyl group, subtending a dihedral angle of 88.1 (1)°, and the di-hydro-pyridine ring adopts a screw-boat conformation. In both compounds, the mol-ecular structure is consolidated by weak C-H⋯O intra-molecular inter-actions formed by the sulfone oxygen atoms, which generate S(5) ring motifs. In the crystal of II, mol-ecules are linked via C-H⋯O hydrogen bonds, generating C(7) chains running along the [100] direction. No significant inter-molecular inter-actions are observed in I.

A Formal (4 + 2) Cycloaddition of Phosphorus Ylides: Synthesis of Aromatic and Heteroaromatic 1,2-Diesters and Diones.

Heteroarylmethylenephosphorus ylides underwent Michael addition with alkynediones and alkynediesters, followed by intramolecular cyclization and elimination of triphenylphosphine oxide to afford 1,2-diaroylbenzenes and 1,2-alkoxycarbonylcarbo- and heterocycles. The analogous (4 + 2) cycloaddition led to the formation of 2,3-diaroylquinolines.

Design, crystal structure determination, molecular dynamic simulation and MMGBSA calculations of novel p38-alpha MAPK inhibitors for combating Alzheimer's disease.

The hallmark of the Alzheimer's disease (AD) is the accumulation of aggregated, misfolded proteins. The cause for this accumulation is increased production of misfolded proteins and impaired clearance of them. Amyloid aggregation and tau hyperphosphorylation are the two proteinopathies which accomplish deprivation of cell and tissue hemostasis during neuropathological process of the AD, as a result of which progressive neuronal degeneration and the loss of cognitive functions. p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in both the events associated with AD: tau protein phosphorylation and inflammation. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Clinical and preclinical evidence implicates the stress related kinase p38α MAPK as a potential neurotherapeutic target. Drug design of p38α MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here we have carried out the synthesis of phenyl sulfonamide derivatives Sulfo (I) and Sulfo (II). Crystal structures of Sulfo (I) and Sulfo (II) were solved by direct methods using SHELXS-97. Sulfo (I) and Sulfo (II) have Rint values of 0.0283 and 0.0660, respectively, indicating good quality of crystals and investigated their ability against p38α MAPK. Docking studies revealed that the Sulfo (I) had better binding affinity (-62.24 kcal/mol) as compared to Sulfo (II) and cocrystal having binding affinity of -54.61 kcal/mol and -59.84 kcal/mol, respectively. Molecular dynamics simulation studies of Sulfo (I) and cocrystal of p38α MAPK suggest that during the course of 30 ns simulation run, compound Sulfo (I) attained stability, substantiating the consistency of its binding to p38α MAPK compared to cocrystal. Binding free energy analysis suggests that the compound Sulfo (I) is better than the cocrystal. Thus, this study corroborates the therapeutic potential of synthesized Sulfo (I) in combatting AD.Communicated by Ramaswamy H. Sarma.

Pd(0)-Catalyzed Intramolecular Heck reaction of 2/3-Aryl(amino)methyl-3/2-bromoindoles: Syntheses of 3,4-Benzo[c]-ß-carbolines, Benzo[4,5]isothiazolo[2,3-a]indole 5,5-Dioxides, and 1,2-Benzo[a]-γ-carbolines.

One-pot synthesis of 3,4-benzo[c]-ß-carbolines was achieved from 2-aryl(tosylamino)methyl-3-bromoindoles via 10 mol % Pd(OAc)2/PPh3-mediated intramolecular Heck coupling using K2CO3 as a base in DMF at 110 °C with concomitant aromatization through an elimination of tosylsulfinic acid. Under identical conditions, the isomeric 3-aryl(tosylamino)methyl-2-bromoindoles upon intramolecular Heck reaction furnished benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxides instead of the expected γ-carbolines. However, synthesis of the expected γ-carboline framework, 3-tosyl-6,9-dihydro-1,2-benzo[a]-γ-carbolines, could be achieved from 3-aryl(tosylamino)methyl-2-bromoindoles containing a mesitylene sulfonyl unit as a protecting group on the indole nitrogen.

Diels-Alder reaction of tetraarylcyclopentadienones with benzo[b]thiophene S,S-dioxides: an unprecedented de-oxygenation vs. sulfur dioxide extrusion.

Diels-Alder reaction of tetraarylcyclopentadienones with benzo[b]thiophene dioxides in xylenes at reflux led to the formation of tetra aryl-substituted dibenzothiophene as well as penta aryl-substituted benzene analogues depending on the influence of aryl substituents present on cyclopentadienones. The intermediate dihydrodibenzothiophene-dioxides underwent aromatization either through de-oxygenation or extrusion of sulfur dioxide to furnish substituted dibenzothiophenes or benzenes.

Divergent Synthesis and Evaluation of the in†vitro Cytotoxicity Profiles of 3,4-Ethylenedioxythiophenyl-2-propen-1-one Analogues.

A new series of 3,4-ethylenedioxythiophene (EDOT)-appended propenones were prepared by condensation reaction and their in vitro cytotoxicity effects were evaluated against five human cancer cell lines. Preliminary structure-activity relationships of EDOT-incorporated 2-propenone derivatives were also established. The EDOT-appended enones demonstrated significant cytotoxicity against human cancer cell lines. The most active analogue, (E)-3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3 p, GI50 =110 nm), severely inhibited the clonogenic potential of cancer cells, and induced cell-cycle arrest in the G2/M phase and caused an accumulation of HCT116 colon cancer cells with >4 N DNA content. Also, 3 p exhibited weak inhibition of the enzymatic activity of human topoisomerase I. Molecular docking studies indicated preferential binding of the compounds to the ATP-binding pocket of the human checkpoint 2 kinase (Chk2) catalytic domain, thus, identifying a novel diaryl 2-propenone chemotype for the development of potent inhibitors of Chk2.

Novel isothiacalothrixin B analogues exhibit cytotoxic activity on human colon cancer cells in vitro by inducing irreversible DNA damage.

Preliminary cytotoxic analysis of sulphur containing isosteric analogues of calothrixin B identified the useful anti-tumour activity of thia/isothiacalothrixin B which necessitated it's biological evaluation in colon and lung cancer cell lines. The isothia analogues induced cytotoxicity of HCT116 in a time-dependent manner and inhibited the clonogenic survival of HCT116 and NCI-H460 cells in a dose-dependent manner comparable to the standard anti-cancer drug camptothecin. Herein employing flow cytometry, we demonstrate that isothiacalothrixin B analogues inhibited proliferation of colon cancer cells by the arrest of cells in S and G2/M phases over a period of 48 hours at a concentration of 5 µM. Our results also suggest that the cytotoxicity of thia analogues of calothrixin B is partially mediated by induction of cellular DNA strand breaks. The UV-Vis spectroscopic studies with CT-DNA revealed groove binding for calothrixin B and its thia analogues wherein subsequent in silico molecular modelling studies indicated preferential binding to the AT-rich regions of minor groove of DNA. Furthermore, thiacalothrixin B caused transcriptional activation of p21waf1/cip1 promoter and upregulation of its protein levels independent of p53. The induction of DNA damage response pathway leads to apoptosis in isothiacalothrixin B but not in thiacalothrixin B treated cells. The isothia analogues SCAB 4 induced DNA strand breaks and cell cycle arrest even after treatment for a short period (i.e., 4 hours) and the cell cycle effects were irreversible. For the first time, this study provides detailed cellular effects on the potential use of isothiacalothrixin B analogues as cytotoxic agents.

Crystal structure of dimethyl 1-oxo-2,4-di-phenyl-1,2-dihydronaphthalene-2,3-di-carboxyl-ate.

In the title compound, C26H20O5, a 1,2-di-hydro-naphthalene derivative, the cyclo-hexa-1,3-diene ring of the 1,2-di-hydro-naphthalene ring system adopts a half-chair conformation. The mean plane of the 1,2-di-hydro-napthalene ring system makes dihedral angles of 86.23 (6) and 64.80 (7)° with two phenyl rings. The carbonyl O atom attached to the di-hydro-naphthalene ring system deviates from the mean plane of the 1,2-di-hydro-naphthalene ring system by 0.618 (1) Å. In the crystal, the mol-ecules are linked into layers parallel to the bc plane via two kinds of C-H⋯O inter-actions, one of which forms a C(10) chain motif running along the c-axis direction and the other forms an R22(6) ring motif. Adjacent layers are further connected by C-H⋯π and offset π-π inter-actions [centroid-centroid distance = 3.6318 (9) Å].

Diels-Alder Reaction of Isobenzofurans/Cyclopentadienones with Tetrathiafulvalene: Preparation of Naphthalene, Fluoranthene, and Fluorenone Derivatives.

Diels-Alder reaction of 1,3-diarylbenzo[c]furan/cyclopentadienone with TTF followed by triflic acid mediated cleavage of the resulting adducts led to the formation of the respective 1,4-diaryl substituted naphthalenes, fluoranthenes, and fluorenones. The photophysical properties of representative diaryl-substituted hydrocarbons are also reported.

Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues.

A series of calothrixin B (2) analogues bearing substituents at the 'E' ring and their corresponding deoxygenated quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities of calothrixins 1, 2, and 15b-p and quinocarbazole analogues were investigated against nine cancer cell lines. The quinocarbazoles 21a and 25a inhibited the catalytic activity of human topoisomerase II. The plasmid DNA cleavage abilities of calothrixins 1, 2, and 15b-p identified compound 15h causing DNA cleavage comparable to that of calothrixin A (1). Calothrixin A (1), 3-fluorocalothrixin 15h and 4-fluoroquinocarbazole 21b induced extensive DNA damage followed by apoptotic cell death. Spectral and plasmid unwinding studies demonstrated an intercalative mode of binding for quinocarbazoles. We identified two promising drug candidates, the 3-fluorocalothrixin B 15h with low toxicity in animal model and its deoxygenated derivative 4-fluoroquinocarbazole 21b as having potent cytotoxicity against NCI-H460 cell line with a GI50 of 1 nM.

Crystal structures of 1-benzene-sulfon-yl-2-methyl-3-(4-nitro-benzoyl)-2,3-di-hydro-1H-indole and 1-benzene-sulfon-yl-2-methyl-3-[(thio-phen-2-yl)carbon-yl]-2,3-di-hydro-1H-indole.

In the title indole derivatives, C22H16N2O5S, (I) and C20H15NO3S2, (II), the sulfonyl-bound phenyl rings are almost orthogonal to the indole ring system, subtending dihedral angles of 88.33 (10) and 87.58 (16)°, respectively. In both compounds, the sulfonyl S atom has a distorted tetra-hedral geometry [O-S-O = 119.98 (9) and N-S-C = 104.01 (8)° for compound (I) and O-S-O = 120.08 (18) and N-S-C = 104.91 (14)° for compound (II)] and the sum of the bond angles at N indicates sp2 hybridization. The mol-ecules of both (I) and (II) feature intra-molecular C-H⋯O hydrogen bonds that generate S(6) ring motifs with the sulfone O atom. In the crystals, mol-ecules of (I) are linked by C-H-O hydrogen bonds, forming R44(18) ring motifs while mol-ecules of (II) are linked by C-H-O and C-H-S hydrogen bonds, forming R22(12) ring motifs. Compound (II) was refined as an inversion twin.

Synthetic Utility of Arylmethylsulfones: Annulative π-Extension of Aromatics and Hetero-aromatics Involving Pd(0)-Catalyzed Heck Coupling Reactions.

A straightforward and general method for the synthesis of annulated thiophene, dibenzothiophene, and carbazoles analogues has been achieved involving alkylation of 2-bromo-1-(phenylsulfonylmethyl)arene/heteroarene with arylmethyl bromides/heteroarylmethyl bromides using t-BuOK as a base in DMF, followed by Pd(0)-mediated intramolecular Heck coupling in the presence of K2CO3 in DMF at 80-140 °C. The attractive feature of this protocol is that a wide variety of π-conjugated heterocycles could be readily accessed by an appropriate choice of arylmethylsulfones and benzylic bromides.

Crystal structures of three 1-oxo-1,2-di-hydro-naphthalene derivatives: dimethyl 4-(4-meth-oxy-phen-yl)-2-(4-methyl-phen-yl)-1-oxo-1,2-di-hydro-naphthalene-2,3-di-carboxyl-ate, dimethyl 1-oxo-2-(pyren-4-yl)-4-(thio-phen-2-yl)-1,2-di-hydro-naphthalene-2,3-di-carboxyl-ate and ethyl 1-oxo-2-phenyl-2,4-bis-(thio-phen-2-yl)-1,2-di-hydro-naphthalene-3-carboxyl-ate.

In the title 1-oxo-1,2-di-hydro-naphthalene derivatives, C28H24O6, (I), C34H22O5S, (II), and C27H20O3S2, (III), the cyclo-hexa-1,3-diene rings of the 1,2-di-hydro-naphthalene ring systems adopt half-chair, boat and half-chair conformations, respectively. The carbonyl O atoms attached to the di-hydro-naphthalene ring systems are each significantly deviated from the mean plane of the 1,2-di-hydro-naphthalene ring system, by 0.6162 (12) Šin (I), 0.6016 (16) Šin (II) and 0.515 (3) Šin (III). The mean planes of the 1,2-di-hydro-naphthalene ring systems make dihedral angles of 85.83 (3), 88.19 (3) and 81.67 (8)°, respectively, with the methyl-phenyl ring in (I), the pyrene ring in (II) and the phenyl ring in (III). In (I), the mol-ecular structure is stabilized by an intra-molecular C-H⋯O hydrogen bond, generating an S(6) ring motif. In the crystal of (I), mol-ecules are linked by an inter-molecular C-H⋯O hydrogen bond, which generates a C(8) zigzag chain running along [100]. Adjacent chains are further connected by C-H⋯π and offset π-π inter-actions [centroid-centroid distance = 3.6572 (9) Å], forming a double-chain structure. In the crystals of (II) and (III), mol-ecules are linked into chain structures by offset π-π inter-actions with centroid-centroid distances of 3.5349 (12) and 3.8845 (13) Šfor (II) and 3.588 (2) Šfor (III). In (II) and (III), the thio-phene rings are orientationally disordered over two sites, with occupancy ratios of 0.69:0.31 for (II), and 0.528 (4):0.472 (4) and 0.632 (5):0.368 (5) for (III).