Sintesis N1-Isopropilteobromin dan N1-Sec-Butilteobromin serta uji aktivitasnya sebagai trakeospasmolitik in vitro

HARIONO, Maywan, Dr. Ratna Asmah Susidarti, M.Si.,Apt

2007 | Tesis | S2 Ilmu Farmasi

Xantin merupakan alkaloid yang mempunyai efek stimulansia ringan dan banyak digunakan sebagai bronkodilator, terutama pada terapi asma. Berdasarkan hubungan struktur dan aktivitas turunan xantin, diketahui bahwa substitusi pada N1 xantin meningkatkan aktivitas dan selektivitasnya sebagai bronkodilator. Tiga senyawa N1-alkilxantin yaitu N1-n-propilteobromin, N1-n-butilteobromin and N1-n-pentilteobromin telah disintesis dan ketiganya mampu menghambat kontraksi otot polos trakea in vitro yang diinduksi dengan histamin, bahkan menunjukkan aktivitas yang lebih kuat daripada teofilin. Tujuan dari penelitian ini adalah untuk mensintesis N1-isopropil- dan N1-sec-butilteobromin serta menguji aktivitasnya sebagai trakeospasmolitik in vitro. Sintesis senyawa tersebut dikerjakan melalui reaksi antara teobromin dengan isopropil- atau sec-butil bromida dalam pelarut basa selama 12 jam. Produk yang terbentuk diekstraksi menggunakan kloroform dan dimurnikan secara kromatografi lapis tipis preparatif. Kemurnian senyawa hasil sintesis diuji dengan KLT, titik lebur dan kromatografi gas, sedangkan struktur kimianya diidentifikasi berdasarkan spektra IR, 1H- dan 13C-NMR, UV dan massa. Hasil identifikasi menunjukkan bahwa senyawa hasil sintesis adalah N1-isopropil- dan N1-sec-butilteobromin dengan rendemen berturut-turut sebanyak 9,4% dan 9,2%. Uji aktivitas trakeospasmolitik dikerjakan dengan menggunakan trakea marmot terisolasi berdasarkan rancangan acak lengkap pola searah latin square. Spasme trakea diinduksi dengan histamin kemudian diberi perlakuan kedua senyawa hasil sintesis dan teofilin sebagai kontrol positif sebanyak 4 kali replikasi. Hasil uji menunjukkan bahwa N1-isopropil- dan N1-sec-butilteobromin memiliki aktivitas trakeospasmolitik terhadap histamin dengan N1-isopropilteobromin (EC50 = 6,47 x 10-2M) memiliki aktivitas lebih lemah sedangkan N1-sec-butilteobromin (EC100 = 2,47 x 10-5M; EC50 = 1,03 x 10-5M) memiliki aktivitas lebih kuat daripada teofilin (EC100 = 7,67 x 10-2M; EC50 = 1,13 x 10-5M).

Xanthine is an alkaloid having a mild stimulant effect and is used widely as a bronchodilator agent, especially for asthma therapy. Based on a structure-activity relationship study on xanthine derivatives, it is known that substitution at N1-xanthine enhance its activity and selectivity as a bronchodilator. Three N1-alkylxanthine, N1-n-propyltheobromine, N1-n-butyltheobromine and N1-n-pentyltheobromine have been synthesized and all of these are able to inhibit tracheal smooth muscle contraction in vitro that was induced by histamine, even better than that of theophylline activities. The aims of present research are to synthesize N1-isopropyl- and N1-sec-butyl theobromine and to evaluate their tracheospasmolytic activities in vitro. The synthesis of compounds was carried out through reaction between theobromine and isopropyl-or sec-butyl bromide in an alkaline medium for 12 hours. The product was extracted by chloroform and purified by a preparative thin layer chromatographic method. The purity of the products was examined by TLC, melting point and gas chromatography, while the chemical structures were identified based on their IR, 1H-and 13C-NMR, UV and mass spectra. The results have shown that the synthetic products are N1-isopropyl- and N1-sec-butyltheobromine with each of yield is 9,4% and 9,2%. Examination of tracheospasmolytic activities was done by an isolated guinea pig tracheal method based on a completly randomized latin square design. Tracheospasmus was induced by histamine and treated with the synthetic products and theophylline as a positive control, each with four replications. The results showed that N1-isopropyl and N1-sec-butyltheobromine had tracheospasmolitic activities toward histamine where N1-isopropyltheobromine (EC50 = 6,47 x 10-2M) was lower and N1-sec-butyltheobromine (EC100 = 2,47 x 10-5M; EC50 = 1,03 x 10-5M) was stronger than that of theophylline(EC100 = 7,67 x 10-2M; EC50 = 1,13 x 10-5M).

Kata Kunci : Xantin,Terapi Asma