Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors

As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a–c, 7a–c, and 8a–c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a–c), meta (7a–c), or para-positon (8a–c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a–c, 7b, and 8a–b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.</p

Physico-chemical properties analysis and QSAR properties of selected potential eight target compounds (I, V-XI) towards PDEδ inhibitors for repression of oncogenic k-Ras.

Physico-chemical properties analysis and QSAR properties of selected potential eight target compounds (I, V-XI) towards PDEδ inhibitors for repression of oncogenic k-Ras.</p

Values of the Condensed local electrophilicity (ElP)/nucleophilicity (NuP) index (e*eV) of selected potential target compounds (V-IX) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.

Values of the Condensed local electrophilicity (ElP)/nucleophilicity (NuP) index (e*eV) of selected potential target compounds (V-IX) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.</p

Values of the Condensed local Softnesses (Hartree*e) of selected potential target compounds (I, X, XI) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.

Values of the Condensed local Softnesses (Hartree*e) of selected potential target compounds (I, X, XI) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.</p

MEP surfaces of selected potential eight target compounds (I, V-XI) utilizing the level of computation wb97xd/6-311++g(d,p).

MEP surfaces of selected potential eight target compounds (I, V-XI) utilizing the level of computation wb97xd/6-311++g(d,p).</p

Structure for some reported KRAS‒PDEδ inhibitors.

The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDEδ, a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDEδ to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDEδ for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDEδ selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.</div

Values of the Condensed local electrophilicity (ElP)/nucleophilicity (NuP) index (e*eV) of selected potential target compounds (I, X-XI) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.

Values of the Condensed local electrophilicity (ElP)/nucleophilicity (NuP) index (e*eV) of selected potential target compounds (I, X-XI) by using wb97xd/6-311++g(d,p) level of theory from CDFT point of view.</p

MM-PBSA calculations of the binding free energy for the eight complexes.

MM-PBSA calculations of the binding free energy for the eight complexes.</p

Molecular docking of the target compounds.

The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDEδ, a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDEδ to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDEδ for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDEδ selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.</div

The RMSD analysis for the entire residues of the eight compounds in complex with their target.

The RMSD analysis for the entire residues of the eight compounds in complex with their target.</p