Investigation of Antifungal Properties of Synthetic Dimethyl-4-Bromo-1-(Substituted Benzoyl) Pyrrolo[1,2-a] Quinoline-2,3-Dicarboxylates Analogues: Molecular Docking Studies and Conceptual DFT-Based Chemical Reactivity Descriptors and Pharmacokinetics Evaluation

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-05, Vol.26 (9), p.2722
• Main Authors: Uppar, Vijayakumar, Chandrashekharappa, Sandeep, Shivamallu, Chandan, P, Sushma, Kollur, Shiva Prasad, Ortega-Castro, Joaquín, Frau, Juan, Flores-Holguín, Norma, Basarikatti, Atiyaparveen I, Chougala, Mallikarjun, Mohan M, Mrudula, Banuprakash, Govindappa, Jayadev, Venugopala, Katharigatta N, Nandeshwarappa, Belakatte P, Veerapur, Ravindra, Al-Kheraif, Abdulaziz A, Elgorban, Abdallah M, Syed, Asad, Mudnakudu-Nagaraju, Kiran K, Padmashali, Basavaraj, Glossman-Mitnik, Daniel
• Format: Article
• Language: English
• Subjects: Amino acids; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacokinetics; Aspartic endopeptidase; Binding; Biological activity; BQ molecules; Candida albicans; Carboxylic Acids - chemical synthesis; Carboxylic Acids - pharmacokinetics; Chemical reactions; Chemistry, Pharmaceutical - methods; conceptual DFT; Density Functional Theory; DFT—density functional theory; Drug Design; Drug development; Drug resistance; Fluconazole; Fluconazole - pharmacology; Fungal infections; Fungi; Fungicides; Hydrogen Bonding; Hydrogen bonds; Immunosuppressive agents; indolizines; Indolizines - chemistry; Ligands; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Molecular Structure; Opportunist infection; Pathogens; Patients; Pharmaceutical industry; Pharmacokinetics; Pharmacology; Protein Conformation; Proteins; pyrrolo[1,2-a] quinolone; Quantitative Structure-Activity Relationship; Quinoline; Quinolines - chemical synthesis; Quinolines - pharmacokinetics; Structure-activity relationships; Therapeutic targets; Thermodynamics; Tropical diseases
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26092722

, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein β-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against that warrants further investigation.