Turunan Asam 6-kloropirazina-2-karboksilat: Sintesis dan Uji Bioaktivitas terhadap Mycobacterium tuberculosis H37Rv

Aijijiyah, Nur Pasca (2020) Turunan Asam 6-kloropirazina-2-karboksilat: Sintesis dan Uji Bioaktivitas terhadap Mycobacterium tuberculosis H37Rv. Masters thesis, Institut Teknologi Sepuluh Nopember.

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Abstract

Munculnya resistensi terhadap obat-obat antituberkulosis dalam bentuk multi drug-resistant (MDR-TB) dan extensively drug-resistant (XDR-TB) adalah permasalahan utama dalam pengobatan tuberkulosis. Obat antituberkulosis terbaru berupa bedakuilin (TMC207) dan nitroimidazol bisiklik (PA-824) memiliki efek samping yang menyebabkan detak jantung yang tidak normal. Pirazinamida atau pirazina-2-karboksamida (3) merupakan salah satu obat antituberkulosis lini pertama, terjadinya mutasi genetik pada bakteri tuberkulosis menyebabkan resistensi terhadap pirazinamida (3). Senyawa-senyawa analog pirazinamida selanjutnya dimanfaatkan sebagai lead compounds dalam pengembangan senyawa-senyawa baru antituberkulosis. Sintesis analog pirazinamida sebagian besar memanfaatkan tionil klorida yang merupakan bahan kimia yang masuk dalam daftar The Chemical Weapons Convention (CWC). Sintesis analog pirazinamida dapat dilakukan dengan reaksi yang melibatkan 1,1’-karbonildiimidazola, tetapi intermediet yang diperoleh kurang reaktif dibandingkan dengan asil klorida. Sintesis karboksamida dapat dilakukan dengan hidroksibenzotriazola, tetapi senyawa ini bersifat eksplosif. 2,4,6-Triklorobenzoil klorida (TCBC) merupakan pereaksi yang digunakan dalam sintesis senyawa ester dan tioester. Penelitian yang dilakukan bertujuan untuk memanfaatkan TCBC dalam sintesis N-(4-etilfenil)pirazina-2-karboksamida (18a), N-sikloheptilpirazina-2-karboksamida (18b), dan N-oktilpirazina-2-karboksamida (18c); serta mengungkap data bioaktivitas amida (18a-c) terhadap bakteri Mycobacterium tuberculosis H37Rv. 6-Kloro-N-(4-etilfenil)pirazina-2-karboksamida (18a), 6-kloro-N-sikloheptilpirazina-2-karboksamida (18b), dan 6-kloro-N-oktilpirazina-2-karboksamida (18c) masing-masing berhasil disintesis dengan rendemen 75, 71, dan 73%. Hasil uji bioaktivitas terhadap M. tuberculosis H37Rv menunjukkan bahwa senyawa (18b) menunjukkan bioaktivitas terbaik diantara amida (18a-c) dengan MIC 6,25-3,13 ppm yang lebih baik daripada pirazinamida (3) dengan MIC 6,25-12,5 µg/mL.
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The emergence of resistance to antituberculosis drugs in the form of multi drug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) is the main problem in tuberculosis treatment. The latest antituberculosis drugs such as bedakuiline (TMC207) and bicyclic nitroimidazole (PA-824) have side effects that cause abnormal heart rhythms. Pyrazinamide or pyrazine-2-carboxamide (3) is one of the first-line antituberculosis drugs, the occurrence of genetic mutations in tuberculosis bacteria causing resistance to pyrazinamide (3). Pyrazinamide analogues are then used as lead compounds in the development of new antitubercular agents. Pyrazinamide analogues synthesis mostly involves thionyl chloride which is a chemical included in the list of The Chemical Weapons Convention (CWC). Pyrazinamide analogues synthesis can be carried out by a reaction involving 1,1'-carbonyldiimidazole, but the intermediates obtained are less reactive than acyl chlorides. Carboxamides synthesis can also be carried out with hydroxybenzotriazole, however this compound is explosive. 2,4,6-Trichlorobenzoyl chloride (TCBC) is a reagent used in the synthesis of esters and thioesters. The research carried out aims to utilize TCBC in the synthesis of N-(4-ethylphenyl)pyrazine-2-carboxamide (18a), N-cycloheptylpyrazine-2-carboxamide (18b), and N-octylpyrazine-2-carboxamide (18c); and reveal the amide bioactivity data (18a-c) against Mycobacterium tuberculosis H37Rv. 6-Chloro-N-(4-ethylphenyl)pyrazine-2-carboxamide (18a), 6-chloro-N-cycloheptylpyrazine-2-carboxamide (18b), and 6-chloro-N-octylpyrazine-2-carboxamide (18c) were successfully synthesized in 75, 71, and 73% yields respectively. The results of the bioactivity test against M. tuberculosis H37Rv showed that the compound (18b) showed the best bioactivity among the amides (18a-c) with a MIC 6.25-3.13 ppm which is better than pyrazinamide (3) with a MIC of 6.25-12.5 µg/mL.

Item Type:	Thesis (Masters)
Additional Information:	RTKi 572.549 Aij t-1 2020 3100020085450
Uncontrolled Keywords:	2,4,6-triklorobenzoil klorida, analog pirazinamida, tuberkulosis
Subjects:	Q Science > QD Chemistry > QD251.2 Chemistry, Organic. Biochemistry
Divisions:	Faculty of Science and Data Analytics (SCIENTICS) > Chemistry > 47101-(S2) Master Thesis
Depositing User:	Nur Pasca Aijijiyah
Date Deposited:	11 Dec 2025 08:16
Last Modified:	11 Dec 2025 08:16
URI:	http://repository.its.ac.id/id/eprint/74478

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