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Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents.
Akhter, Gowsia; Hamid, Hinna; Beg, Mirza A; Tantray, Mushtaq A; Dhawan, Bharti; Alam, Mohammad Sarwar; Selvapandiyan, Angamuthu; Kalicharan, Sharma.
Afiliação
  • Akhter G; Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, 110062 New Delhi, India.
  • Hamid H; Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, 110062 New Delhi, India.
  • Beg MA; Department of Molecular Medicine, School of Interdisciplinary Sciences and Technology, Jamia Hamdard, Hamdard Nagar, New Delhi, India, 110062.
  • Tantray MA; Chemistry Research Lab, Department of Chemistry, Govt. Degree College Baramulla, J&K 193103, India.
  • Dhawan B; Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, 110062 New Delhi, India.
  • Alam MS; Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, 110062 New Delhi, India.
  • Selvapandiyan A; Department of Molecular Medicine, School of Interdisciplinary Sciences and Technology, Jamia Hamdard, Hamdard Nagar, New Delhi, India, 110062.
  • Sayeed Ur Rehman; Department of Biochemistry, School of Chemical and Life Science, Jamia Hamdard, Hamdard Nagar, 110062 New Delhi, India.
  • Kalicharan S; Delhi Pharmaceutical Science and Research University, New Delhi, India.
Curr Med Chem ; 2024 Oct 02.
Article em En | MEDLINE | ID: mdl-39360547
ABSTRACT

INTRODUCTION:

More than 20 protozoan species of Leishmania are responsible for causing Leishmaniasis, an infection spread by blood-feeding phlebotomine sandflies. A narrow pool of drugs is currently available rendering the current drug stratagem to treat this infection . Development of novel, less toxic, and more effective regimens is thus a need of the hour. Design and synthesis of benzo[d]imidazole carboxamides as agents to combat Leishmaniasis are also required.

METHODS:

14 benzo[d]imidazole carboxamides were synthesized and gauged against L. donovani promastigotes and intramacrophage amastigote forms. All of the tested compounds exhibited significant anti-promastigote properties with IC50 well below 10 uM. Compounds 4a, 4b, and 4d, showing the highest anti-parasitic activity against promastigote forms (IC50 0.91- 1.33 µM), were also found to be associated with better anti-leishmanial potential (IC50 0.78- 1.67 µM) against the intramacrophage amastigotes comparable to Amphotericin-B (0.13 µM), a drug used for Leishmaniasis. Compound (4a), namely N-(2-(trifluoromethyl)-1Hbenzo[ d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole, was found to be most potent against L. donovani amastigotes among all the tested compounds, and demonstrated better antileishmanial properties (IC50 0.78 µM) when compared to the standard. Compound 4a was also assessed for its toxicity profile against THP-1 human monocytic cells. To establish the molecular target(s) in silico, molecular docking studies were performed against cysteine protease, a putative virulence factor of Leishmania parasites, and nucleoside diphosphate kinase, an enzyme with a critical role in nucleotide recycling, also associated with resistance in Leishmania strains. Compound 4a showed better binding affinity than the standard to these targets; furthermore, the molecular dynamic simulation studies further affirmed the stability of compound 4a, within the active site of the targets. In vitro, cysteine protease inhibitory activity (IC50 8.53 µM) using Bz-Arg-AMC hydrochloride fluorogenic peptide substrate established the promising potential of 4a as a cysteine protease inhibitor.

RESULT:

Computational ADMET analysis indicated appropriate pharmacokinetic profile and physicochemical characteristics for all members of the synthesized library.

CONCLUSION:

Both in vitro and in silico studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)benzo[d][1,3]-5-carboxamide-dioxole 4a can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight Leishmania donovani.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Curr Med Chem / Curr. med. chem / Current medicinal chemistry Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Índia País de publicação: Emirados Árabes Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Curr Med Chem / Curr. med. chem / Current medicinal chemistry Assunto da revista: QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Índia País de publicação: Emirados Árabes Unidos