Sintesis Senyawa Turunan Calkon Sebagai Senyawa Antimalaria, Antikanker dan Antimikroba

HERY SUWITO, Prof. Drs. Jumina, Ph.D, Prof. Dr Mustofa, M.Kes, Prof. Dr. Ni Nyoman Tri Puspaningsih, M.Si.

2015 | Disertasi | S3 Kimia

Sintesis dan uji aktivitas antimalaria, antikanker dan antimikroba senyawa turunan metoksi-4'-amino calkon telah dilakukan dalam penelitian ini. Turunan calkon didesain agar dapat menghambat interaksi PfFd-PfFNR pada apikoplas Plasmodium falciparum. Sebagai antikanker dan antimikroba, molekul target didesain sebagai inhibitor enzim dihidropteroat sintase (DHPS) yang penting dalam biosintesis asam folat untuk perkembangbiakan sel. Senyawa calkon disintesis menggunakan reaksi Claisen-Schmidt. Struktur molekul senyawa hasil sintesis dikarakterisasi berdasarkan data spektroskopi. Enzim PfFd diisolasi dari rekombinan E. coli JM105 (pTrs99a), sedang enzim PfFNR diisolasi dari rekombinan E. coli TG1 (pTrs99A). Aktivitas inhibisi interaksi PfFNR-PfFd senyawa hasil sintesis dilakukan menggunakan Cyt-c assay. Uji aktivitas antikanker digunakan sel kanker payudara T47D menggunakan MTT-assay, sedang aktivitas antimikroba digunakan Eschericia coli ATCC 25923, Staphylococcus aureus ATCC 25922, dan Candida albicans ATCC 10231 dengan metode cakram kertas. Sintesis turunan calkon diperoleh rendemen 42-98%. Senyawa hasil sintesis mampu menghambat interaksi PfFd-PfFNR dengan aktivitas inhibisi antara 4,49 - 50%. Senyawa MT-3 memiliki aktivitas inhibisi terbesar. Berdasarkan eksperimen docking senyawa hasil sintesis memiliki afinitas yang lebih besar dalam membentuk interaksi elektrostatik dengan maize leaf-PfFNR dibandingkan terhadap PfFd, dan dibuktikan bahwa aliran elektron selama proses respirasi berasal dari PfFNR ke PfFd. Pada uji antikanker, senyawa hasil sintesis memiliki harga IC50 5,38 - 48,77 µg/mL, dengan senyawa yang paling poten adalah MT-7. Gugus amino memegang peranan penting bagi aktivitas antikanker, gugus metoksi perannya kurang signifikan, sedang atom brom menurunkan aktivitas antikanker. Uji antimikroba diperoleh hasil bahwa senyawa MT-4 memiliki potensi yang baik untuk digunakan sebagai agen antimikroba yang memiliki spektrum luas. Hasil docking memperlihatkan bahwa senyawa uji memiliki afinitas yang lebih besar terhadap DHPS S. aureus dibandingkan terhadap E. coli dan diasumsikan dapat bertindak sebagai inhibitor kompetitif bagi hidroksimetilpterin pirofosfat.

Synthesis and antimalarial, anticancer, and antimicrobial activity test of methoxy-4'-amino chalcone derivatives have been conducted in this research. The prepared chalcone derivatives were designed as inhibitor of the interaction of PfFdPfFNR in the apicoplast of Plasmodium falciparum. As anticancer and antimicrobial agents, the synthesized compounds were designed as inhibitor of dihydropteroate synthase (DHPS), which plays a crucial role in the folic acid biosynthesis for cell proliferation. The chalcone derivatives were synthesized using Claisen-Schmidt reaction. Their structures were elucidated based on the spectroscopy evidences. Enzyme PfFd was isolated from E. coli JM105 (pTrs99a), whereas PfFNR was isolated from E. coli TG1 (pTrs99a). Inhibition of PfFNR-PfFd interaction activity of the prepared compounds was determined by Cyt-c assay. Anticancer activity test was examined by MTT assay using breast cancer cell line T47D, while the antimicrobial activity was tested by paper disc inhibition method using Eschericia coli ATCC 25923, Staphylococcus aureus ATCC 25922, and Candida albicans ATCC 10231. The yields of the desired compounds were in the range of 42-98%. The prepared compounds were able to inhibit the interaction of PfFd-PfFNR in range of 4.49 - 50%. Compound MT-3 exhibited the strongest inhibition activity. Based on docking experiment, the prepared compounds showed greater affinity to maize leafPfFNR than to PfFd. It was proved that electron flow during respiration proceeds from PfFNR to PfFd. The anticancer test showed that the IC50 values of the prepared compounds were in the range of 5.38 - 48.77 µg/mL, and MT-7 was the most potent. Amino group played an important role for anticancer activity, methoxy group played insignificant role, whereas bromo group decreased the anticancer activity. The antimicrobial test showed that MT-4 possessed good potential to be used as a wide spectrum antimicrobial agent. Docking experiment showed that the prepared compounds showed greater affinity to DHPS S. aureus than to E. coli, and it was assumed that they can act as a competitive inhibitor of hydroxymethylpterin pyrophosphate.

Kata Kunci : turunan metoksi-4'-amino calkon, antimalaria, antikanker, antimikroba