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

被引：22

作者：

Uppar, Vijayakumar ^{[1
]}

Chandrashekharappa, Sandeep ^{[2
,3
]}

Shivamallu, Chandan ^{[4
]}

Sushma, P. ^{[3
]}

Kollur, Shiva Prasad ^{[5
]}

Ortega-Castro, Joaquin ^{[6
]}

Frau, Juan ^{[6
]}

Flores-Holguin, Norma ^{[7
]}

Basarikatti, Atiyaparveen I. ^{[1
]}

Chougala, Mallikarjun ^{[8
]}

Mohan, M. Mrudula ^{[4
]}

Banuprakash, Govindappa ^{[9
]}

Jayadev ^{[9
]}

Venugopala, Katharigatta N. ^{[10
,15
]}

Nandeshwarappa, Belakatte P. ^{[11
]}

Veerapur, Ravindra ^{[12
]}

Al-Kheraif, Abdulaziz A. ^{[13
]}

Elgorban, Abdallah M. ^{[14
]}

Syed, Asad ^{[14
]}

Mudnakudu-Nagaraju, Kiran K. ^{[4
]}

Padmashali, Basavaraj ^{[1
]}

Glossman-Mitnik, Daniel ^{[7
]}

机构：

[1] Rani Channamma Univ, Sch Basic Sci, Dept Chem, Belagavi 591156, Karnataka, India

[2] Inst Stem Cell Sci & Regenerat Med, NCBS, TIFR, GKVK Campus Bellary Rd, Bengaluru 560065, Karnataka, India

[3] Natl Inst Pharmaceut Educ & Res NIPER Raebareli, Dept Med Chem, Lucknow 226002, Uttar Pradesh, India

[4] JSS Acad Higher Educ & Res, Dept Biotechnol & Bioinformat, Fac Life Sci, Mysore 570015, Karnataka, India

[5] Amrita Sch Arts & Sci, Dept Sci, Amrita Vishwa Vidyapeetham, Mysuru 570026, Karnataka, India

[6] Univ Illes Balears, Dept Quim, E-07122 Palma De Malllorca, Spain

[7] Ctr Invest Mat Avanzados, Lab Virtual NANOCOSMOS, Dept Medio Ambiente & Energia, Chihuahua 31136, Chih, Mexico

[8] JSS Coll Arts Commerce & Sci Autonomous, Dept Biotechnol, Mysore 570025, Karnataka, India

[9] SJB Inst Technol, Dept Chem, Bengaluru 560060, Kengeri, India

[10] King Faisal Univ, Dept Pharmaceut Sci, Coll Clin Pharm, Al Hasa 31982, Saudi Arabia

[11] Davangere Univ, Dept Studies Chem, Davangere 577007, Karnataka, India

[12] Malawi Univ Sci & Technol, Malawi Inst Technol, Dept Met & Mat Engn, POB 5916, Limbe, Malawi

[13] King Saud Univ, Dept Dent Hlth, Coll Appl Med Sci, Dent Biomat Res Chair, POB 10219, Riyadh 11433, Saudi Arabia

[14] King Saud Univ, Dept Bot & Microbiol, Coll Sci, POB 2455, Riyadh 11451, Saudi Arabia

[15] Durban Univ Technol, Fac Sci Appl, Dept Biotechnol & Food Technol, ZA-4001 Durban, South Africa

来源：

MOLECULES | 2021年 / 26卷 / 09期

关键词：

BQ molecules; pyrrolo[1; 2-a] quinolone; indolizines; molecular docking; DFT— density functional theory; conceptual DFT; Candida albicans; antifungal drug; CANDIDA-ALBICANS; FORCE FIELD; MEDICINAL CHEMISTRY; LARVICIDAL ACTIVITY; EFFICIENT SYNTHESIS; INDOLIZINE ANALOGS; DRUG-LIKENESS; BASIS-SETS; DERIVATIVES; DESIGN;

D O I：

10.3390/molecules26092722

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Candida albicans, 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 C. albicans 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 screening 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 C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein beta-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 C. albicans showed inhibitory potential in the concentration of 0.4 mu g for BQ-06, 07 and 08, 0.8 mu g for BQ-01, 03, and 05, 1.6 mu g for BQ-04 and 12.5 mu g for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 mu g. 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 C. albicans that warrants further investigation.

引用

页数：20