Marole M. Maluleka

Advances in Metal-Catalyzed Cross-Coupling Reactions of Halogenated Quinazolinones and Their Quinazoline Derivatives

Halogenated quinazolinones and quinazolines are versatile synthetic intermediates for the metal-catalyzed carbon–carbon bond formation reactions such as the Kumada, Stille, Negishi, Sonogashira, Suzuki-Miyaura and Heck cross-coupling reactions or carbon-heteroatom bond formation via the Buchwald-Hartwig cross-coupling to yield novel polysubstituted derivatives. This review presents an overview of the application of these methods on halogenated quinazolin-4-ones and their quinazolines to generate novel polysubstituted derivatives.

Synthesis and Photophysical Properties of 2-Aryl-6,8-bis(arylethenyl)-4-methoxyquinolines

Iodine-methanol mediated oxidative-aromatization of 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones afforded the corresponding 2-aryl-6,8-dibromo-4-methoxy-quinolines in high yield and purity. The isomeric 1-(2-amino-3,5-dibromophenyl)-3-aryl-2-propen-1-ones reacted with iodine in methanol afford in a single pot operation the corresponding 2-aryl-6,8-dibromo-4-methoxyquinoline (major) and 2-aryl-6,8-dibromoquinolin-4(1H)-one (minor) products that were separated in sequence by column chromatography on silica gel. Suzuki-Miyaura cross-coupling of the 6,8-dibromo-4-methoxyquinoline derivatives with excess arylvinylboronic acids afforded the corresponding 2-aryl-6,8-bis(2-arylethenyl)-4-methoxyquinolines. The absorption and fluorescence properties of these compounds were also determined.

Spectroscopic, DFT, and XRD Studies of Hydrogen Bonds in N-Unsubstituted 2-Aminobenzamides

The structures of the mono- and the dihalogenated N-unsubstituted 2-aminobenzamides were characterized by means of the spectroscopic (1H-NMR, UV-Vis, FT-IR, and FT-Raman) and X-ray crystallographic techniques complemented with a density functional theory (DFT) method. The hindered rotation of the C(O)–NH2 single bond resulted in non-equivalence of the amide protons and therefore two distinct resonances of different chemical shift values in the 1H-NMR spectra of these compounds were observed. 2-Amino-5-bromobenzamide (ABB) as a model confirmed the presence of strong intramolecular hydrogen bonds between oxygen and the amine hydrogen. However, intramolecular hydrogen bonding between the carbonyl oxygen and the amine protons was not observed in the solution phase due to a rapid exchange of these two protons with the solvent and fast rotation of the Ar–NH2 single bond. XRD also revealed the ability of the amide unit of these compounds to function as a hydrogen bond donor and acceptor simultaneously to form strong intermolecular hydrogen bonding between oxygen of one molecule and the NH moiety of the amine or amide group of the other molecule and between the amine nitrogen and the amide hydrogen of different molecules. DFT calculations using the B3LYP/6-311++G(d,p) basis set revealed that the conformer (A) with oxygen and 2-amine on the same side predominates possibly due to the formation of a six-membered intramolecular ring, which is assisted by hydrogen bonding as observed in the single crystal XRD structure.

Novel polycarbo-substituted alkyl (thieno[3,2-c]quinoline)-2- carboxylates : synthesis and cytotoxicity studies

Direct one-pot base-promoted conjugate addition–elimination of 6,8-dibromo-4-chloroquinoline-3-carbaldehyde with methyl mercaptoacetate and subsequent cyclization afforded methyl [(6,8-dibromothieno[3,2-c]quinoline)]-2-carboxylate. The latter undergoes Suzuki-Miyaura cross-coupling with arylboronic acids to yield exclusively the corresponding alkyl [(6,8-diarylthieno[3,2-c]quinoline)]-2-carboxylates,. The cytotoxicity of the prepared compounds was evaluated against the human breast cancer cell line MCF-7 using the MTT assay. The effects of compounds 2, 3c and 4d on cell kinetics were further determined using the xCELLigence Real Time Cell Analysis (RTCA) system. In both the MTT assay and Real Time Cell Analysis, the compounds inhibited cancer cell growth in a dose- and time-dependent manner. Furthermore, on the basis of the calculated LC50 values, the compounds compared favourably with nocodazole, a well-established anticancer drug.

Benzofuran–appended 4-aminoquinazoline hybrids as epidermal growth factor receptor tyrosine kinase inhibitors: synthesis, biological evaluation and molecular docking studies

Abstract A series of 2-arylbenzo[b]furan–appended 4-aminoquinazoline hybrids were prepared and evaluated for cytotoxicity in vitro against the human lung cancer (A549), colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A) and cervical cancer (HeLa) cell lines. Compounds 10d and 10j exhibited significant cytotoxicity against the C3A and Caco-2 cell lines and induced apoptosis in these cell lines. Likewise, compounds 10d and 10e exhibited significant inhibitory activity towards epidermal growth factor receptor-tyrosine kinase phosphorylation (IC50 values of 29.3 nM and 31.1 nM, respectively) against Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 10 into EGFR-TK active site suggests that they bind to the region of EGFR like Gefitinib does.

Synthesis, Evaluation for Cytotoxicity and Molecular Docking Studies of Benzo[c]furan-Chalcones for Potential to Inhibit Tubulin Polymerization and/or EGFR-Tyrosine Kinase Phosphorylation

A series of 2-arylbenzo[c]furan-chalcone hybrids 3a–y have been synthesized and evaluated for antiproliferative effects against the human breast cancer (MCF-7) cell line and for its potential to induce apoptosis and also to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. Most of these compounds exhibited moderate to significant antigrowth effects in vitro against the MCF-7 cell line when compared to the reference standard actinomycin D. The capabilities of the most cytotoxic benzofuran-chalcone hybrids 3b and 3i, to induce apoptosis, have been evaluated by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The experimental and molecular docking results suggest that the title compounds have the potential to exhibit inhibitory effects against tubulin polymerization and epidermal growth factor receptor tyrosine kinase (EGFR-TK) phosphorylation. The modeled structures of representative compounds displayed hydrophobic interactions as well as hydrogen and/or halogen bonding with the protein residues. These interactions are probably responsible for the observed increased binding affinity for the two receptors and their significant antigrowth effect against the MCF-7 cell line.

Crystal structure of 1-(4-chlorophenyl)-6,8-diphenyl-1H-pyrazolo[4,3-c]quinoline, C28H18ClN3

Abstract C28H18ClN3, monoclinic, P21/c, (no. 14) a = 5.9519(2) Å, b = 8.0511(3) Å, c = 43.4071(14) Å, β = 90.001(2)°, V =2080.04(12) Å3, Z = 4, Rgt(F) = 0.066, wRref(F2) = 0.190, T = 173 K.

Crystal structure of 6,8-diphenyl-2-(4-fluorophenyl)-2,3-dihydroquinolin-4(3H)-one, C27H20FNO

Abstract C27H20FNO, monoclinic, P21/n (no. 14), a = 13.1620 Å, b = 13.8779 Å, c = 11.1618 Å, β = 99.710(1)°, V = 2009.62(6) Å3, Z = 4, Rgt(F) = 0.0436, wRref(F2) = 0.1310, T = 173(2) K.

Crystal structure of (1E,4E)-1,5-bis(4-chlorophenyl)penta-1,4-dien-3-one, C17H12Cl2O

Abstract C17H12Cl2O, monoclinic, P21/c, a = 17.2845(14) Å, b = 14.2007(11) Å, c = 5.8795(5) Å, β = 99.088(3)°, V = 1425.0(2) Å3, Z = 4, Rgt(F) = 0.0567, wRref(F2) = 0.1395, T = 263 K.

The crystal structure of 2-(4-methoxyphenyl)-6,8-diphenyl-4-(phenylamino)quinazoline — acetonitrile (1/1), C35H28N4O

Abstract C35H28N4O, triclinic, P1̅ (no. 2), a = 10.5972(11) Å, b = 11.0497(12) Å, c = 12.0241(12) Å, α = 89.499(4)°, β = 77.169(4)°, γ = 79.758(4)°, V = 1350.2(2) Å3, Z = 2, Rgt(F) = 0.0717, wRref(F2) = 0.1542, T = 173 K.