Aktivitas antimikroba In Vitro senyawa turunan fumarat dan kajian hubungan struktur aktivitasnya
WIEDYANINGSIH, Chairun, Dr.Drs. Mustofa, M.Kes.,Apt
2005 | Tesis | S2 Ilmu Kedokteran Dasar dan BiomedisSalah satu problem pengobatan infeksi adalah terjadinya resistensi obat antimikroba yang sering digunakan dalam praktek klinis. Oleh karena itu, penting untuk menemukan calon obat baru, khususnya senyawa penuntun yang dapat menjadi dasar berpijak dalam pengembangan obat baru. Tujuan utama dalam penelitian ini adalah mengevaluasi aktivitas antimikroba dan mengkaji hubungan kuantitatif struktur-aktivitas (HKSA) pada satu seri (sembilan) senyawa turunan fumarat. Kesembilan senyawa tersebut adalah: etil-N-fenil fumaramat (A), metil-N-fenil fumaramat (B), etil-N-benzil fumaramat (C), metil-N-anisil fumaramat (D), metil-N-benzil fumaramat (E), etil-N-anisil fumaramat (F), Ca-benzil fumaramat (G), Na-benzil fumaramat (H), dan N-benzil-propil- fumaramat (I). Uji aktivitas antimikroba dilakukan dengan menentukan konsentrasi hambatan minimum (KHM) senyawa uji secara in vitro dengan metode makrobroth dilusi terhadap bakteri Pseudomonas aeruginosa dan Salmonella enteritidis serta jamur Aspergillus niger, Penicillium sp dan Candida albicans. Kajian HKSA dilakukan terhadap hubungan antara parameter elektronik berupa muatan bersih atom (q) berdasarkan metode semiempirik AM1 dari senyawa uji dengan aktivitasnya sebagai antijamur. Hasil uji aktivitas antibakteri menunjukkan bahwa senyawa uji kurang aktif terhadap kedua jenis bakteri. Namun, kecuali bentuk garamnya, senyawa turunan fumarat menunjukkan aktivitasnya terhadap ketiga jamur uji, dengan KHM sekitar 37,5-100 mg/mL. Di antara senyawa uji, senyawa C, D, F dan I adalah yang paling poten sebagai antijamur. Model persamaan HKSA terbaik yang diperoleh dari analisis regresi multilinear adalah: A niger: Log 1/KHM = -57,102 + 2,305.(qC6) +26,331.(qC7) + 611,974.(qC10) + 496,619.(qO2) – 59,759. (qO3); (n = 7 ; r2 = 0,999; SE = 0,1792; Fhitung/Ftabel = 54,09). Penicillium sp: Log 1/KHM = -14,921 + 2,175.(qC6) + 201,464.(qC10) + 158,076.(qO2) – 11,115. (qO3): (n = 7; r2 = 0,996; SE = 0,2478; Fhitung/Ftabel = 28,53). C. albicans: Log 1/KHM = -38,195 + 1,664.(qC6) + 17,475.(qC7) + 474,912.(qC10) + 361,082. (qO2): (n = 7; r2 = 0,985; SE = 0,3321; Fhitung/Ftabel = 7,45)
One of the problems in infection therapy is the existence of drugs resistance strains for most of antimicrobial drugs currently used in clinic practice. Therefore, it is important to find new antimicrobial candidate compounds, particularly new leads, which would be able to become the basis for developing new drugs. The purpose of this study is to evaluate antimicrobial activity and perform Quantitative Structure- Activity Relationships (QSAR) of a series (nine compounds) of fumaric derivates. Those compounds are: ethyl-N-phenyl fumaramate (A), methyl-Nphenyl fumaramate (B), ethyl-N-benzyl fumaramate (C), methyl-N-anisyl fumaramate (D), methyl-N-benzyl fumaramate (E), ethyl-N-anisyl fumaramate (F), Ca-benzyl fumaramate(G), Na-benzyl fumaramate(H), N-benzyl-propyl-fumaramate (I). The compounds were assayed in vitro for antimicrobial activity using macrobroth dilution method against two strains of bacteria i.e: Pseudomonas aeruginosa and Salmonella enteritidis, and three strains of fungi i.e: Aspergillus niger, Penicillium sp and Candida albicans. The minimum inhibitory concentration (MIC) was determined for the tested compounds as a parameter of activity. QSAR analysis between atomic net charges (q) as predictors and antifungal activity in the form of log (1/MIC) was performed by computational chemistry method using semi-empirical molecular orbital AM1 calculation. All of the compounds tested were not sufficiently active against both bacteria strains used. However, with exception of the salt form, the compounds tested have shown significant activity against the three species of fungi employed with MIC values ranging between 37,5-100 mg/mL. Among the compounds tested, compounds C, D, F and I were found to be the most potent against fungi. The best QSAR model has been determined by multiple linear regression analysis giving equation: A niger: Log 1/KHM = -57.102 + 2.305.(qC6) +26.331.(qC7) + 611.974.(qC10) + 496.619.(qO2) – 59.759. (qO3) : (n = 7 ; r2 = 0.999; SE = 0.1792; Fcalculated/Ftable = 54.09). Penicillium sp: Log 1/KHM = -14.921 + 2.175.(qC6) + 201.464.(qC10) + 158.076.(qO2) – 11.115. (qO3) : (n = 7; r2 = 0.996; SE = 0.2478; Fcalculated/Ftable = 28.53). C. albicans: Log 1/KHM = -38.195 + 1.664.(qC6) + 17.475.(qC7) + 474.912.(qC10) + 361.082. (qO2) : (n = 7; r2 = 0.985; SE = 0.3321; Fcalculated/Ftable = 7.45)
Kata Kunci : Farmakologi,Obat Antimikroba,Analisis HKSA,KHM, MIC, QSAR analysis, Antimicrobial, fumaric derivates
