Design, synthesis of pyridine coupled pyrimidinone/pyrimidinthione as anti-MRSA agent: Validation by molecular docking and dynamics simulation

Swamy, S. Nanjunda; Bindhu, S.; Renganathan, R.R. Arun; Nagashree, S.; Karthik, C.S.; Mallu, P.; Ravishankar, V.

doi:10.1080/07391102.2021.1968496

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…Medicinal chemistry techniques were employed to synthesize the newly designed compounds, which were characterized using IR, NMR, and HR-MS techniques. Standard drugs such as streptomycin, kanamycin, and linezolid were utilized in the biological evaluation of these compounds, which were tested against MRSA bacterial strains to investigate their resistance [152]. The MIC study of these compounds was performed using the microbroth dilution method.…”

Section: -(3h)-quinazolinonesmentioning

confidence: 99%

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

Ambade,

Gupta,

Bhole

et al. 2023

Molecules

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Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to β-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-β-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (β-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded β-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-β-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.

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Section: -(3h)-quinazolinonesmentioning

confidence: 99%

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

Ambade,

Gupta,

Bhole

et al. 2023

Molecules

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“…RMSD adalah indikasi dari perubahan konformasi kompleks ligan-protein (Jiang et al, 2019). Semakin rendah nilai RMSD maka semakin stabil proteinnya (Aier et al, 2016;Alhadrami et al, 2020;Nanjundaswamy et al, 2021). Grafik RMSD kedua senyawa disajikan pada Gambar 2.…”

Section: Simulasi Dinamika Molekularunclassified

“…Hal ini menandakan bahwa perubahan konformasi pada kedua senyawa terjadi cukup besar. Kestabilan konformasi protein dapat dipastikan secara jelas dengan melakukan simulasi dinamika molekular pada jangka waktu yang lebih lama (Nanjundaswamy et al, 2021;Verma et al, 2021).…”

Section: Simulasi Dinamika Molekularunclassified

Penambatan Molekul dan Simulasi Dinamika Molekular Kandungan Minyak Kayu Manis dan Minyak Serai Dapur Sebagai Antibakteri Methicillin Resistant Staphylococcus aureus

et al. 2022

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Meluasnya penyebaran Methicillin Resistant Staphylococcus aureus (MRSA) yang kebal terhadap antibiotik β-laktam membuat penelitian untuk menemukan senyawa aktif yang memiliki potensi sebagai antibakteri MRSA menjadi penting. Salah satu penelitian yang dapat dilakukan adalah studi penambatan molekul. Studi penambatan molekul telah dilakukan menggunakan senyawa bahan alam dari minyak kayu manis dan minyak serai dapur dengan reseptor enzim Penicillin Binding Protein 2a (PBP2a). Studi ini memiliki tujuan untuk memprediksi kemampuan senyawa bahan alam dari kedua minyak atsiri tersebut sebagai antibakteri MRSA. Penambatan molekul dilakukan menggunakan perangkat lunak (software) AutoDock 4.2. Hasil penelitian menunjukkan bahwa senyawa dengan potensi sebagai antibakteri paling besar adalah trans-β-kariofilen dan geranil asetat dengan energi ikat sebesar -6,12 dan -5,11 kkal/mol dan konstanta inhibisi sebesar 32,69 dan 180,41 µM. Hasil penambatan molekul kemudian dilanjutkan dengan simulasi dinamika molekular. Hasil simulasi dinamika molekular menunjukkan bahwa kedua senyawa memiliki nilai Root Mean Square Deviation (RMSD) yang tinggi.Molecular Docking and Molecular Dynamics Simulation of Cinnamon Oil and Kitchen Lemongrass Oil as Antibacterial Agent Against Methicillin-Resistant Staphylococcus aureus. The spread of Methicillin-Resistant Staphylococcus aureus (MRSA) caused the research for its antibiotic to become more pressing than ever. One of the research that can be conducted is a molecular docking study. A molecular docking study of natural products from cinnamon and lemongrass oil with Penicillin Binding Protein 2a (PBP2a) enzyme was conducted. This study aims to predict the ability of each natural product to become an MRSA antibiotic. The molecular docking was conducted with AutoDock 4.2 software. The result shows that β-caryophyllene and geranyl acetate have the most potential to become MRSA antibiotics with binding energies of -6.12 kcal/mol and -5.11 kcal/mol and inhibition constants of 32.69 μM and 180.41 µM, respectively. The results of molecular docking were validated using molecular dynamic simulation. Molecular dynamic simulation shows that both complexes have a high root mean square deviation (RMSD) value.

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“…Dihydrofolate reductase (DHFR) is an essential enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate, and its inhibition disrupts DNA replication and eventually causes cell death . Pyrimidines, diaminopyrimidines, and related structures are intensively investigated for their DHFR inhibitory activity leading to highly selective and potent anti-MRSA agents. , Trimethoprim (TMP), 5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine ( A ), is a well-known antimicrobial agent. , It inhibits DHFR in bacterial and protozoal cells and has been used clinically since the 1960s (Figure ). It is usually used alone or in combination with sulfamethoxazole. − The majority of Gram-positive Staphylococcus aureus (S.…”

Section: Introductionmentioning

confidence: 99%

“…3 Pyrimidines, diaminopyrimidines, and related structures are intensively investigated for their DHFR inhibitory activity leading to highly selective and potent anti-MRSA agents. 4,5 Trimethoprim (TMP), 5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine (A), is a well-known antimicrobial agent. 6,7 It inhibits DHFR in bacterial and protozoal cells and has been used clinically since the 1960s (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation

Mansour,

El-Sherbeny,

Al-Omary

et al. 2023

ACS Omega

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Two hybrid series of pyrazole-clubbed pyrimidines 5a−c and pyrazole-clubbed pyrazoline compounds 6a,b and 7 were designed as attractive scaffolds to be investigated in vitro and in vivo for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. From the results of the in vitro antibacterial screening, compound 5c showed excellent activity (minimal inhibitory concentration, MIC = 521 μM) when compared with that of the reference antibiotic levofloxacin (MIC = 346 μM). The inhibition of the target dihydrofolate reductase (DHFR) enzyme by compounds 4 and 5a−c (IC 50 = 5.00 ± 0.23, 4.20 ± 0.20, 4.10 ± 0.19, and 4.00 ± 0.18 μM, respectively) was found to be better than the reference drug trimethoprim (IC 50 = 5.54 ± 0.28 μM). Molecular modeling simulation results have justified the order of activity of all the newly synthesized compounds as DHFR enzyme inhibitors, and compound 5c exhibited the best binding profile (−13.6169386 kcal/mol). Hence, the most potent inhibitor of the DHFR enzyme, 5c, was chosen to be evaluated in vivo for its activity in treating MRSA-induced keratitis in rats and that, in turn, significantly (P < 0.0001) reduced infection in rats when compared to MRSA-treated group results.

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Design, synthesis of pyridine coupled pyrimidinone/pyrimidinthione as anti-MRSA agent: Validation by molecular docking and dynamics simulation

Cited by 8 publications

References 23 publications

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

Penambatan Molekul dan Simulasi Dinamika Molekular Kandungan Minyak Kayu Manis dan Minyak Serai Dapur Sebagai Antibakteri Methicillin Resistant Staphylococcus aureus

New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation

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