Modeling of Quinoacridinium Derivatives as Antitumor Agents using a QSAR analysis

A QSAR analysis has been performed on a compound series of 1-11 quinoacridinium derivatives as internal test compounds, and compounds of 12-15 quinoacridinium derivatives as external test compounds. The electronic descriptors used in this study were atomic net charge (q), dipole moment (μ), ELUMO, EHOMO, polarizability (α), and Log P. They were calculated through HyperChem for Windows 8.0 software using semi-empirical PM3 method. The antitumor activity (IC50) of quinoacridinium derivative compounds was obtained from literature. Furthermore, the model of QSAR equation was analyzed through RML method which produced the best QSAR equation model: Log IC50 = -13.010 + 15.338(qC3) - 4.31(qC4) - 155.308(qC9) + 33.626(qC11) + 26.626(qC12) + 24.631(qC14) - 0.228(μ) - 0.621(ELUMO) - 0.066(α) + 0.233(Log P). The model of QSAR equation has a correlation coefficient n = 11, (r) = 1.00, (r2) = 1.00, SE = 0, and PRESS = 0.003. Among 28 compounds of quinoacridinium derivative which were designed, only 15 compounds, namely 16, 19-20, 22-28, 30-32, 39, and 40 compounds, have been recommended to be synthesized in the laboratory

SINTESIS SENYAWA t-KALKON BAHAN DASAR SENYAWA TABIR SURYA

A novel method for the synthesis of t-chalcone as material start of sunscreen compounds through aldol condensation reaction was introduced using NaOH/EtOH as a catalyst and solvent. The structures of the t-chalcone of product were confirmed by IR, GC-MS and 1H-NMR spectrosfotomete

Identifikasi Struktur Komponen Senyawa Kimia Kulit Batang Ketapang (Terminalia catappa L.)

Ketapang (Terminalia catappa L.) is a type of flowering plant that has been widely used by the community, especially in traditional medicine. This research aims to identify the chemical compound components of Ketapang bark using Virgin Coconut Oil (VCO) solvent. Research methods include making VCO, maceration extraction, solubility testing, identification of chemical compound components using FTIR and GC-MS. The mass of VCO is 744.32 grams (14.88% soaking). The mass of Ketapang bark extract weighed 183.88 grams (0.63% soaking). The solubility test shows that VCO and extracts are generally nonpolar. Identification results using FT-IR show that VCO has C-H, C=O and C-O groups, while ketapang bark extract has aliphatic –CH, C=O, C-O, C-OH, C-N and aromatic C-H groups. Identification using GC-MS showed that VCO had 112 peaks, among the 112 peaks that had a similarity index of 80% there were 14 peaks, while the ketapang bark extract had 190 peaks and 11 peaks had a similarity index. Thus, it can be concluded that the components of the VCO compound are decanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, pentadecanoic acid, 2-monocaprin (2TMS derivative), palmitelaidic acid, palmitic acid, and stearic acid. Meanwhile, Ketapang stem bark extract contains heptadecanoic acid, (z) oleic acid, elaidic acid, 1-ethoxy-4'-methoxy-2,2'-binaptyl-1,4-dione, eikosan, 7-methyl-z-tetradeken- 1-ol-acetate, beta-alanine, sarcosine, 1-aminomethyl-cyclododecanol, and dodecanoic acid, 2,3-dihydroxypropyl ester.Ketapang (Terminalia catappa L.) merupakan jenis tumbuhan berbunga yang telah digunakan masyarakat secara luas khususnya dalam pengobatan tradisional. Penelitian ini bertujuan untuk mengidentifikasi komponen senyawa kimia kulit batang ketapang menggunakan pelarut Virgin Coconut Oil (VCO). Metode penelitian meliputi pembuatan VCO, ekstraksi maserasi, uji kelarutan, identifikasi komponen senyawa kimia menggunakan FTIR dan GC-MS. Massa VCO sebanyak 744,32 gram (rendamen 14,88%). Massa ekstrak kulit batang ketapang seberat 183,88 gram (rendamen 0,63%). Uji kelarutan menunjukkan VCO dan ekstrak secara umum bersifat nonpolar. Hasil identifikasi menggunakan FT-IR menunjukkan VCO memiliki gugus C-H, C=O dan C-O, sedangkan ekstrak kulit batang ketapang memiliki gugus –CH alifatik, C=O, C-O, C-OH, C-N, dan C-H aromatik. Identifikasi menggunakan GC-MS menunjukkan VCO memiliki 112 puncak, diantara 112 puncak yang memiliki indeks similaritas mencapai 80% sebanyak 14 puncak, sedangkan ekstrak kulit batang ketapang terdapat 190 puncak dan yang memiliki indeks similaritas sebanyak 11 puncak. Dengan demikian, dapat disimpulkan komponen senyawa VCO yaitu asam dekanoat, asam dodekanoat, asam tridekanoat, asam miristat, asam pentadekanoat, 2-monocaprin (2TMS derivative), asam palmitelaidat, asam palmitat, dan asam stearat. Sedangkan ektsrak kulit batang ketapang mengandung asam heptadekanoat, asam (z) oleat, asam elaidat, 1-etoksi-4’-metoksi-2,2’-binaptyl-1,4-dion, eikosan, 7-metil-z-tetradeken-1-ol-asetat, beta-alanin, sarkosin, 1-aminometil-siklododekanol, dan asam dodekanoat, 2,3-dihidroksipropil ester

SYNTHESIS OF ANTIMALARIAL 3-(2-HYDROXYETHYL)-2-METHYL-1,10-PHENANTHROLINE-4-OL FROM 8-AMINOQUINOLINE

It has been conducted the synthesis of 3-(2-hydroxyethyl)-2-methyl-1,10-phenanthroline-4-ol was carried out from 8-aminoquinoline which are expected to posses antimalarial activity. The experiment perfomed consisted of two steps i.e (1) reaction of 8-aminoquinoline with 2-acetyl-butyrolactone and (2) cyclization of the resulted 3-[1-(quinolin-8-ylamino)-ethylidene]-4,5-dihydro-furan-2-one. The reaction of 8-aminoquinoline with 2-acetyl-butyrolactone was performed in toluene at reflux for 6 hours in the presence of p-toluensulfonic acid as catalyst. This reaction gave 3-[1-(quinolin-8-ilamino)-etiliden]-4,5-dihidro-furan-2-on in 60.6% yield. The cyclization of 3-[1-(quinoline-8-ylamino)-ethyliden]-4,5-dihydro-furan-2-one was conducted in cloroform at reflux for 4 hours in the presence of H2SO4 as catalyst and also tween 80 as transfer phase catalyst to give 3-(2-hydroxy-ethyl)-2-methyl-1,10-phenanthroline-4-ol in 76.2% yield. Identification of the products were carried out by means of infra red (IR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) spectroscopy, and mass spectroscopy (MS).   Keywords: antimalarial, 8-aminoquinoline, cyclization, 1,10-phenantrolin

SINTESIS DAN UJI AKTIVITAS SENYAWA (1)-N-(n-BUTIL)- DAN (1)-N-(t-BUTIL)-1,10-FENANTROLINIUM SEBAGAI SENYAWA POTENSIAL ANTIMALARIA BARU

The synthesis of (1)-N-(n- buthyl)- dan (1)-N-(t-buthyl)-1,10-phenanthrolinium with 1,10-phenanthroline monohydrate as starting material through two steps has been carried out. The first step of reaction is chlorination and bromination of n-buthyl-alcohol/t-buthyl alcohol using HCl and HBr, respectively. The result of reaction is nbuthyl bromide 2 (colourless liquid, 70.92%) and t-buthyl chloride 4 (colourless liquid, 92.36%), respectively. The second step of reaction is alkylation of 1,10-phenanthroline 5 using n-buthyl bromide and t-buthyl chloride reagents that its was refluxed for 21 and 23 h, respectively. The results of reaction are (1)-N-(n- buthyl)-1,10fenantrolinium bromida 6 and (1)-n-(t-buthyl)-1,10-fenantrolinium chloride 7 in yield from 84.70% and 78.16%, respectively. The results of testing in in vitro antiplasmodial activity at chloroquine-resistant P. falciparum FCR3 strain to (1)-N-(n-buthyl)- and (1)-N-(t-buthyl)-1,10- phenanthrolinium obtained that (1)-N-(n-buthyl)-1,10phenanthrolinium bromide 6 has higher antimalarial activity (IC50 : 0.03±0.01 µM) than antimalarial activity of (1)-n-(t-buthyl)-1,10-phenanthrolinium chloride 7 (IC50 : 2.09±0.08 µM). While, the results of testing in in vitro antiplasmodial activity at chloroquine-resistant P. falciparum D10 strain to (1)-N-(n-buthyl)- and (1)-N-(t-buthyl)1,10-f phenanthrolinium obtained that (1)-N-(n-butil)-1,10- phenanthrolinium bromide 6 has higher antimalarial activity (IC50 : 1.40±0.82 µM) than antimalarial activity of (1)-n-(t-buthyl)-1,10- phenanthrolinium chloride 7 (IC50 : 2.24±0.05 µ

In vitro anticancer activity of N-benzyl 1,10-phenanthroline derivatives on human cancer cell lines and their selectivity

This research was conducted to evaluate the anticancer activity of new compounds of benzyl-1,10-phenanthroline derivatives and their selectivity. In vitro anticancer activity of 11 benzyl-1,10-phenanthroline derivatives were conducted on three human cancer cell lines, cervical cancer (HeLa), myeloma (NS-1), and breast cancer (MCF-7) using MTT-based cytotoxicity assay. The cytotoxicity of each compound was assessed to normal Vero cell line by the same method. The in vitro anticancer activity and cytotoxicity was expressed by the concentration inhibiting 50% of the cell growth (IC50), and the selectivity index (SI) was determined by calculating ratio of the IC50 on Vero cell line and the human cancer cell lines. The results showed that among the 11 compounds tested, the (1)-N-(4-butoxybenzyl)-1,10-phenanthrolinium bromide exhibited the best in vitro anticancer activity with an IC50 27.602.76 μM on HeLa, 6.425.53 μM on NS-1 and 9.442.17 μM on MCF-7 cell lines. Its SI were 377.65 39.97 on HeLa, 6158.72 5306.34 on NS-1 and 1140.11 261.85 on MCF-7 cell lines. This study demonstrated that (1)-N-(4-butoxybenzyl)-1,10-phenanthrolinium bromide possessed a potential in vitro anticancer activity on cancer cell lines with high selectivity

SINTESIS DAN UJI AKTIVITAS ANTIMALARIA SENYAWA (1)-N-BENZIL-1,10- FENANTROLINIUM BROMIDA

A synthetic methods was employed to prepare (1)-N-benzyl)-1,10-phenanthroliniumbromide 4 from 1,10phenanthroline 3 and benzylchloride 1 through substitution and alkylation reactions. The compound (1)-Nbenzyl)-1,10-phenanthroliniumbromide 4 was tested through antiplasmodial test. The benzylbromide 2 was synthesized through substitution reaction of benzylchloride 1 and NaBr which has a yield of 74.25%. The (1)-N-benzyl)-1,10-phenanthroliniumbromide 4 was synthesized from 1,10-phenanthroline 3 using benzylbromide 2 reagents which refluxed for 8 hours with 84.04% yields. The results of testing in in vitro antiplasmodial activity at chloroquine-resistant Plasmodium falciparum FCR3 strain to (1)-N-benzyl)-1,10-  phenanthroliniumbromide 4 has high antimalarial activity (IC50 : 0.10±0.04 µM

QUANTITAVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR) OF ANTIMALARIAL 1,10-PHENANTHROLINE DERIVATIVES COMPOUNDS

Quantitative Electronic Structure-Activity Relationship (QSAR) analysis of a series of 1,10-phenanthroline derivatives as antiplasmodial compounds have been conducted using atomic net charges (q), dipole moment (μ) ELUMO, EHOMO, polarizability (α) and log P as the descriptors. The descriptors were obtained from computational chemistry method using semi-empirical PM3. Antiplasmodial activities were taken as the activity of the drugs  against  chloroquine-resistant Plasmodium falciparum FCR3 strain and are presented as the value of ln (1/IC50) where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best model of QSAR model was determine by multiple linear regression method and giving equation of QSAR: ln 1/IC50  =  3.732 + (5.098) qC5 + (7.051) qC7 + (36.696) qC9 + (41.467) qC11 -(135.497) qC12 + (0.332) μ -                    (0.170) α + (0.757) log P. The equation was significant on the 95% level with statistical parameters: n=16; r=0.987; r2= 0.975; SE=0.317;  Fcalc/Ftable = 15.337 and gave the PRESS=0.707. Its means that there were only a relatively few deviations between the experimental and theoretical data of antimalarial activity.   Keywords: QSAR, antimalarial, semi-empirical method, 1,10-phenanthroline

SYNTHESIS AND ANTIPLASMODIAL ACTIVITY TESTING OF (1)-N-ALKYL- AND (1)-N-BENZYL-6-NITRO-1,10-PHENANTHROLINIUM SALTS AS NEW POTENTIAL ANTIMALARIAL AGENTS

The synthesis of 5-nitro-1,10-phenanthroline hydrate 2 derivatives from 1,10-phenanthroline monohydrate as starting material has been carried out. The 5-nitro-1,10-phenanthroline hydrate 2 was obtained through nitration reaction using H2SO4 and HNO3 as catalyst and reagent, respectively. Synthesis of (1)-N-alkyl-6-nitro- and (1)-N-benzyl-6-nitro-1,10-phenanthrolinium have been prepared using dimethyl sulphate (DMS), diethyl sulphate (DES), benzyl chloride, benzyl bromine, and benzyl iodide. The reagents of benzyl bromine, and benzyl iodide were synthesized from benzyl chloride using NaBr in ethanol absolute and NaI in acetone, respectively. The five compounds of 5-nitro-1,10-phenanthroline hydrate 2 derivatives were conducted to evaluate the in vitro antiplasmodial activity. The in vitro antiplasmodial was evaluated on strains of Plasmodium falciparum FCR-3 resistant chloroquine and D10 sensitive chloroquine. The 50% inhibition concentration (IC50) of the five compounds ranged from 2.41±1.41 to 0.07±0.01 μM. The results showed that the (1)-N-benzyl-6-nitro-1,10-phenanthrolinium iodide had highest antiplasmodial activity

SYNTHESIS AND ANTIPLASMODIAL ACTIVITY TESTING OF (1)-N-(4-METHOXYBENZYL)-1,10-PHENANTHROLINIUM BROMIDE

Synthesis of (1)-N-(4-methoxybenzyl)-1,10-phenanthroline bromide from 1,10-phenanthroline monohydrate and 4-methoxybenzaldehyde as starting material and evaluation of its antiplasmodial activities have been carried out. The 4-methoxybenzyl alcohol was prepared from 4-methoxy-benzaldehyde using sodium borohydride (NaBH4) reagent and ethanol absolute solution. The mixture was refluxed for 3 h. To yield colorless dilution compound with 90.41 % in efficiency. Furthermore, bromination of 4-methoxybenzyl alcohol with phosphorus bromide (PBr3) was conducted by refluxing for 3 h. The product of this reaction was yellow liquid of 4-methoxybenzyl bromide, 79.03% yield and 95.34 % purity. The final step of reaction was benzylation of 1,10-phenanthroline monohydrate with 4-methoxybenzyl bromide reagent. It was conducted by refluxing in aceton for 8 h at 55 oC. The yield of the reaction was (1)-N-(4-methoxybenzyl)-1,10-phenanthroline bromide (77.63%). It is pink solid form, and its melting point is 192-193 oC. Identification of the product was carried out by means of GC-MS, IR and 1H-NMR spectrometers. The in vitro antiplasmodial activity on chloroquine-resistant Plasmodium falciparum FCR-3 strain and chloroquine sensitive P. falciparum D10 strain for (1)-N-(4-methoxybenzyl)-1,10-phenanthroline bromide were determined by microscopic method. The result showed that after 72 h incubation, it has IC50 0.93±0.02 µM and 1.21±0.09 µM, respectively.   Keywords: 1,10-phenanthroline,  (1)-N-(4-methoxybenzyl)-1,10-phenanthroline bromide, 4 methoxybenzaldehyde, antiplasmodial activitie