In Silico ADME Screening and Evaluation of Antimicrobial and Antimycobacterial Activities of 3,5-Diphenyl Pyrazoline Derivatives

Yıl 2021, , 184 - 191, 20.08.2021

Begüm Evranos Aksöz , Fatma Kaynak Kaynak Onurdağ , Erkan Aksöz , Selda Özgen

https://doi.org/10.22312/sdusbed.872130

Öz

Objective: The unconscious widespread use of antibiotics leads to the development of resistance to antibiotics. When resistance to an antibiotic develops, it now either shows less efficacy or loses its effect completely at that antibiotic treatment dose. While the development of resistance to antibiotics increases rapidly, the need for the development of new antibiotics rises every day. For this purpose, in this study, antimicrobial and antitubercular effects of some compounds in the pyrazoline structure were investigated. The physicochemical properties and drug-likeness of the compounds are quite important for determining whether a compound can be used as a drug or not. Physicochemical properties and drug-likeness of the synthesized compounds were evaluated and the relevance for Lipinski’s rules was determined. Material-Method: Drug-likeness properties of the synthesized compounds were determined using online Swiss ADME tool. Antitubercular activity is detected by microplate alamar blue assay. Antimicrobial activity is tested by microdilution method. Results: All compounds obeyed the Lipinski’s rules, some of with no violation, some of with one violation. Compounds B7, B10 and B11 provided Lipinski’s rules with one violation. Other compounds ensured Lipinski’s rules with no violation. All compounds were predicted to have high gastrointestinal absorption. As the compounds generally have high lipophilicity, it was predicted that all compounds except B12 can cross the blood brain barrier. Conclusion: Synthesized compounds were mostly found to be more effective against Enterococcus faecalis, Enterococcus faecalis isolate and Candida albicans. Compound B10 demonstrated the best antimicrobial activity against Enterococcus faecalis isolate with a 16µg/mL MIC value. 

Anahtar Kelimeler

Pyrazoline, antimycobacterial, antimicrobial, in silico ADME

Synthesis of 3,5-Diphenyl Pyrazoline Derivatives, In Silico ADME Screening, Evaluation of Antimicrobial and Antimycobacterial Activities

Öz

Özet
Amaç: Antibiyotiklere direnç gelişimi hızla artarken, her geçen gün yeni antibiyotik geliştirme ihtiyacı da artmaktadır. Bu amaçla, bu çalışmada pirazolin yapısındaki bazı bileşiklerin antimikrobiyal ve antitüberküloz etkileri araştırılmıştır. Bileşiklerin fizikokimyasal özellikleri ve ilaç özelliklerine benzerliği, bir bileşiğin ilaç olarak kullanılıp kullanılamayacağını belirlemek için oldukça önemlidir. Sentezlenen bileşiklerin fizikokimyasal özellikleri, ilaç özelliklerine benzerliği ve Lipinski kurallarına uygunluğu belirlendi. Materyal-Metod: Sentezlenen bileşiklerin ilaç özelliklerine benzerliği çevrimiçi İsviçre ADME aracı kullanılarak belirlendi. Antitüberküloz aktivite, mikroplaka alamar mavisi deneyi ile saptandı. Antimikrobiyal aktivite mikrodilüsyon yöntemi ile test edildi. Bulgular: Tüm bileşikler, bazıları hiç ihlal olmadan, bazıları da bir ihlalle Lipinski kurallarına uydu. B7, B10 ve B11 bileşikleri Lipinski'nin kurallarını bir ihlal ile sağlamıştır. Diğer bileşikler, Lipinski'nin kurallarının tamamını ihlalsiz olarak sağlamıştır. Tüm bileşiklerin yüksek gastrointestinal absorbsiyona sahip olduğu tahmin edildi. Bileşikler genel olarak yüksek lipofilisiteye sahip olduğundan, B12 dışındaki tüm bileşiklerin kan beyin bariyerini geçebileceği tahmin edildi. Sonuç: Sentezlenen bileşiklerin çoğunlukla Enterococcus faecalis, Enterococcus faecalis izolatı ve Candida albicans'a karşı daha etkili olduğu bulunmuştur. Bileşik B10, 16µg/mL MIC değeri ile Enterococcus faecalis izolatına karşı en iyi antimikrobiyal aktiviteyi sergilemiştir.
Anahtar kelimeler: Pirazolin, antimikobakteriyel, antimikrobiyal, in siliko ADME





Abstract
Objective: While the development of resistance to antibiotics increases rapidly, the need for the development of new antibiotics rises every day. For this purpose, in this study, antimicrobial and antitubercular effects of some compounds in the pyrazoline structure were investigated. The physicochemical properties and drug-likeness of the compounds are quite important for determining whether a compound can be used as a drug or not. Physicochemical properties and drug-likeness of the synthesized compounds were evaluated and the relevance for Lipinski’s rules was determined. Material-Method: Drug-likeness properties of the synthesized compounds were determined using online Swiss ADME tool. Antitubercular activity is detected by microplate alamar blue assay. Antimicrobial activity is tested by microdilution method. Results: All compounds obeyed the Lipinski’s rules, some of with no violation, some of with one violation. Compounds B7, B10 and B11 provided Lipinski’s rules with one violation. Other compounds ensured Lipinski’s rules with no violation. All compounds were predicted to have high gastrointestinal absorption. As the compounds generally have high lipophilicity, it was predicted that all compounds except B12 can cross the blood brain barrier. Conclusion: Synthesized compounds were mostly found to be more effective against Enterococcus faecalis, Enterococcus faecalis isolate and Candida albicans. Compound B10 demonstrated the best antimicrobial activity against Enterococcus faecalis isolate with a 16µg/mL MIC value.
Keywords: Pyrazoline, antimycobacterial, antimicrobial, in silico ADME

Anahtar Kelimeler

Pyrazoline, antimycobacterial, antimicrobial, in silico ADME

Kaynakça

• REFERENCES 1. Ventola CL. The antibiotic resistance crisis: Part 1: causes and threats. P. T. 2015;40: 277-83.
• 2. Windels EM, Michiels JE, Van denBergh B, Fauvart M, Michiels J. Antibiotics: combatting tolerance to stop resistance. mBio. 2019;10:e02095-19.
• 3. Yıldırım M. Enterococci and infections caused by enterococci. Düzce Tıp Fak. Derg. 2007; 2:46-52.
• 4. Çoğulu D, Uzel A, Önçağ Ö, Aksoy SC, Eronat C. Evaluation of antibiotic susceptibility of enterococcus faecalis isolated from deciduous and permanent tooth root canals. Hacettepe Diş Hek. Fak. Derg. 2008;32:39-44.
• 5. World Health Organisation. Tuberculosis [Internet]. [cited 2020 March 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/tuberculosis
• 6. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017;7:42717.
• 7. Auwers K, Cauer E. 1 -and 2 -pyrazolines. Justus Liebigs Ann. Chem. 1929;470:284-12.
• 8. Kumar S, Meenakshi, Kumar S, Kumar P. Synthesis and antimicrobial activity of some (3-phenyl-5-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl) methanones: new derivatives of 1,3,5-trisubstituted pyrazolines. Med. Chem. Res. 2013;22: 433-39.
• 9. Karad SC, Purohit VB, Raval DK. Design, synthesis and characterization of fluoro substituted novel pyrazolylpyrazolines scaffold and their pharmacological screening. Eur. J. Med. Chem. 2013;84:51-58.
• 10. Dawane BS, Konda SG, Shaikh BM, Chobe SS, Khandare NT, Kamble VT, Bhosale RB. synthesis and in vitro antimicrobial activity of some new 1-thiazolyl-2-pyrazoline derivatives. Int. J. Pharm. Sci. Rev. Res. 2010;1:44-48.
• 11. Abbas A, Naseer MM. Synthesis and anti-inflammatory activity of new N-acyl-2-pyrazolines bearing homologous alkyloxy side chains. Acta Chim. Slov. 2014;61:792-02.
• 12. Abdel-Sayed MA, Bayomi SM, El-Sherbeny MA, Abdel-Aziz NI, ElTahir KE, Shehatou GS et al. Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibition activities and molecular docking study of pyrazoline derivatives. Bioorg. Med. Chem. 2016;24:2032-42.
• 13. Mathew B, Suresh J, Anbazhagan S. Synthesis, preclinical evaluation and antidepressant activity of 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides. EXCLI Journal. 2014;13:437-45.
• 14. Evranos Aksoz, B, Baysal I, Yabanoglu-Ciftci S, Djikic T, Yelekci K, Ucar G, et al. Synthesis and screening of human monoamine oxidase-a inhibitor effect of new 2-pyrazoline and hydrazone derivatives. Arch Pharm. 2015;348:743-56.
• 15. Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS). Performance standards for antimicrobial susceptibility testing 6th informational supplement. CLSI M100-S16, Clinical and Laboratory Standards Institute, 940 West Valley Road, Wayne, Pennsylvania, USA, 2016.
• 16. Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS). Reference method for broth dilution antifungal susceptibility testing of yeast approved standard, M27-A, Clinical and Laboratory Standards Institute, 940 West Valley Road, Wayne, Pennsylvania, USA, 2008.
• 17. Evranos-Aksöz B, Onurdağ FK, Özgacar SÖ. Antibacterial, antifungal and antimycobacterial activities of some pyrazoline, hydrazone and chalcone derivatives. Z. Naturforsch. C. 2015;70:183-89.
• 18. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A, et al. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate alamar blue assay. J. Clin. Microbiol. 1998;36:362-66.
• 19. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001;4:3-26.
• 20. Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999;1:55-68.
• 21. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002;45:2615-23.
• 22. Egan WJ, Merz KM, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 2000;43:3867-77.
• 23. Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J. Med. Chem. 2001;44:1841-46.
• 24. Mishra S, Dahima R. In-vitro ADME studies of TUG-891, a GPR-120 inhibitor using Swiss ADME predictor, J. Drug Deliv. Ther. 2019;9:366-69.
• 25. Kerns EH, Di L. Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization. Academic Press; 2008.