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Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies.

Mondal SK, Mondal NB, Banerjee S, Mazumder UK - Indian J Pharmacol (2009)

Bottom Line: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM.The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively.The methods were found to be very useful for day-to-day ADME studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Jadavpur University, India.

ABSTRACT

Unlabelled: In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies.

Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies.

Materials and methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low).

Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = -5.53 +/- 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 +/- 0.13% while metabolism by Phase-I enzymes for 1 hour at 37 degrees C revealed that 36.07 +/- 4.15% of the compound remained after metabolism.

Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

No MeSH data available.


Related in: MedlinePlus

Structure of 2-(2-Methylquinolin-4-ylamino)-N-phenylacetamide
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Figure 0001: Structure of 2-(2-Methylquinolin-4-ylamino)-N-phenylacetamide

Mentions: Leishmaniasis is a global health problem especially in tropical and subtropical countries and approximately 350 million people are estimated to be prone to this fatal disease.[5] But there are few drugs developed as of yet, which can counteract the problem efficiently. Moreover, the existing antileishmanial compounds bear toxicity especially to heart and liver.[6] In continuation of our research for lead identification of antileishmanial agents, several indolylquinoline derivatives were synthesized[7] and evaluated, both in vitro and in vivo, against promastigote and amastigote forms of parasite of Leishmania donovani[8–10] The compound, 2-(2′′-dichloroacetamidobenzyl)-3-(3′-indo yl)-quinoline, having significant antileishmanial activity was further undertaken for structure activity relationship.[7–10] As a result, a number of analogs were prepared and the compound, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide (henceforth termed as S-4, Figure 1) was found to be significantly more effective than sodium antimony gluconate in reducing the parasite burden both in spleen and liver.[1112]


Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies.

Mondal SK, Mondal NB, Banerjee S, Mazumder UK - Indian J Pharmacol (2009)

Structure of 2-(2-Methylquinolin-4-ylamino)-N-phenylacetamide
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875737&req=5

Figure 0001: Structure of 2-(2-Methylquinolin-4-ylamino)-N-phenylacetamide
Mentions: Leishmaniasis is a global health problem especially in tropical and subtropical countries and approximately 350 million people are estimated to be prone to this fatal disease.[5] But there are few drugs developed as of yet, which can counteract the problem efficiently. Moreover, the existing antileishmanial compounds bear toxicity especially to heart and liver.[6] In continuation of our research for lead identification of antileishmanial agents, several indolylquinoline derivatives were synthesized[7] and evaluated, both in vitro and in vivo, against promastigote and amastigote forms of parasite of Leishmania donovani[8–10] The compound, 2-(2′′-dichloroacetamidobenzyl)-3-(3′-indo yl)-quinoline, having significant antileishmanial activity was further undertaken for structure activity relationship.[7–10] As a result, a number of analogs were prepared and the compound, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide (henceforth termed as S-4, Figure 1) was found to be significantly more effective than sodium antimony gluconate in reducing the parasite burden both in spleen and liver.[1112]

Bottom Line: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM.The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively.The methods were found to be very useful for day-to-day ADME studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Jadavpur University, India.

ABSTRACT

Unlabelled: In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies.

Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies.

Materials and methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low).

Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = -5.53 +/- 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 +/- 0.13% while metabolism by Phase-I enzymes for 1 hour at 37 degrees C revealed that 36.07 +/- 4.15% of the compound remained after metabolism.

Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

No MeSH data available.


Related in: MedlinePlus