Formulasi Obat Ginekologi Berbasis Senyawa Kompleks Co(II), Ni(II), Cu(II), dan Zn(II) - Arilhidrazon

Alam, Yusuf Syahril (2026) Formulasi Obat Ginekologi Berbasis Senyawa Kompleks Co(II), Ni(II), Cu(II), dan Zn(II) - Arilhidrazon. Doctoral thesis, Institut Teknologi Sepuluh Nopember.

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Abstract

Kanker serviks merupakan neoplasma ginekologis dengan tingkat morbiditas dan mortalitas yang signifikan secara global, khususnya di negara berkembang. Strategi profilaksis dan terapi kuratif telah dilakukan namun tidak dapat mengeradikasi dan mengobati kanker tingkat metastasis. Agen kemoterapi klinis masih berbasis platina yang menunjukkan resistansi seluler dan toksisitas sistemik. Kondisi ini menyoroti urgensi pengembangan alternatif terapeutik yang lebih aman dan efektif. Penelitian ini mengusulkan formulasi agen sitostatika baru berupa senyawa kompleks yang melibatkan logam bioesensial, yaitu Co(II), Ni(II), Cu(II), dan Zn(II). Logam tersebut dikhelasi dengan empat ligan arilhidrazon, yakni benzoilhidrazon (L1D), tiosemikarbazon (L2D), toluik hidrazon (L3D), dan isonikotinoil hidrazon (L4D). Kedua puluh senyawa telah berhasil disintesis melalui sistem refluks dengan yield sebesar 20,74%-96,98%. Elusidasi NMR menunjukkan kesesuaian lingkungan proton dan karbon terhadap hipotesis struktur. Analisis FTIR mengindikasikan bahwa seluruh senyawa, kecuali Co-L1D, bertautomerisasi keto atau tioketo. Selain itu, terdapat ikatan koordinasi berupa M-N dan M-O pada bilangan gelombang 421-476 cm-1 dan 519-615 cm-1. Pergeseran spektrum UV-Vis ke panjang gelombang yang lebih besar menunjukkan transisi batokromik pada senyawa kompleks. Analisis massa (ESI-MS) mengindikasikan stoikiometri logam–ligan 1:1 dan 1:2. Hasil tersebut didukung dengan analisis unsur yang menunjukkan kesesusaian komposisi eksperimen dan teoretis. Data TGA menunjukkan pola dekomposisi bertahap dengan residu akhir berupa oksida atau sulfida logam serta karbon residual. Data difraksi sinar-X serbuk dan proses refinement mengindikasikan bahwa senyawa bersifat polikristalin dan memiliki kemiripan karakteristik kristalografi material standar. Kajian ADME memaparkan bahwa mayoritas sampel (ligan dan senyawa kompleks) memenuhi aturan Lipinski sehingga berpotensi sebagai kandidat obat oral. Evaluasi aktivitas sitotoksik terhadap sel kanker serviks HeLa dengan metode PrestoBlue menunjukkan bahwa senyawa Cu-L1D memiliki aktivitas penghambatan terbaik dengan IC50 sebesar 0,54 μg/mL (1,52 μM).
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Cervical cancer is a gynecological neoplasm with significant global morbidity and mortality rates, particularly in developing countries. Although prophylactic strategies and curative therapies have been implemented, they remain insufficient to eradicate and effectively treat metastatic-stage cancer. Current clinical chemotherapeutic agents are still predominantly platinum-based, which exhibit cellular resistance and systemic toxicity. These limitations highlight the urgent need for the development of safer and more effective alternative therapeutic agents. This study proposes the formulation of novel cytostatic agents in the form of coordination complexes involving bioessential metal ions, namely Co(II), Ni(II), Cu(II), and Zn(II). These metal ions were chelated with four arylhydrazone ligands, namely benzoylhydrazone (L1D), thiosemicarbazone (L2D), tolylhydrazone (L3D), and isonicotinoylhydrazone (L4D). A total of twenty compounds were successfully synthesized via a reflux method with yields ranging from 20.74% to 96.98%. NMR elucidation confirmed the consistency between the observed proton and carbon environments and the proposed molecular structures. FTIR analysis indicated that all compounds, except Co-L1D, exist in keto or thio-keto tautomeric forms. In addition, metal–ligand coordination bonds (M–N and M–O) were observed in the regions of 421–476 cm⁻¹ and 519–615 cm⁻¹. The bathochromic shift in the UV–Vis spectra further confirmed ligand-to-complex electronic transitions. ESI-MS analysis indicated metal-to-ligand stoichiometries of 1:1 and 1:2. These results were supported by elemental analysis, which demonstrated good agreement between experimental and theoretical compositions. Thermogravimetric analysis (TGA) revealed stepwise decomposition patterns, yielding final residues consisting of metal oxides or sulfides and residual carbon. Powder X-ray diffraction (PXRD) analysis and refinement processes indicated that the compounds are polycrystalline in nature and exhibit crystallographic features comparable to standard reference materials. ADME studies demonstrated that most ligands and metal complexes comply with Lipinski’s rule of five, suggesting their potential as orally active drug candidates. Cytotoxic evaluation against cervical cancer HeLa cells using the PrestoBlue assay revealed that the Cu-L1D complex exhibited the highest inhibitory activity, with an IC50 value of 0.54 μg/mL (1,52 μM).

Item Type:	Thesis (Doctoral)
Uncontrolled Keywords:	Arilhidrazon; Ginekologis; Kanker Serviks; PrestoBlue; Senyawa Kompleks; Arylhydrazone; Gynecological; Cervical Cancer; PrestoBlue; Complexes
Subjects:	Q Science Q Science > QD Chemistry Q Science > QD Chemistry > QD251.2 Chemistry, Organic. Biochemistry Q Science > QD Chemistry > QD471 Chemical compounds - Structure and formulas R Medicine > R Medicine (General) R Medicine > RG Gynecology and obstetrics
Divisions:	Faculty of Science and Data Analytics (SCIENTICS) > Chemistry > 47001-(S3) PhD Thesis
Depositing User:	Yusuf Syahril Alam
Date Deposited:	05 Aug 2026 03:46
Last Modified:	05 Aug 2026 03:46
URI:	http://repository.its.ac.id/id/eprint/144009

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