Microwave synthesis and antimalarial screening of novel 4-amino benzoic acid (PABA)-substituted pyrimidine derivatives as Plasmodium falciparum dihydrofolate reductase inhibitors

Choudhury, Ayesha Aktar Khanam; Vinayagam, Sathishkumar; Adhikari, Nayana; Ghosh, Surajit Kumar; Kamaraj, Sattu

doi:10.1007/s13205-022-03236-w

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…In case of aliphatic amines substitution (both R 1 & R 2 ), it was observed that an increase in chain length of substitution enhanced the antimalarial activity and vice versa. For example, C1 ( R 1 : diethylamine & R 2 : butylamine) showed high antimalarial activity but compounds A1 ( R 1 : dimethylamine & R 2 : ethylamine), A2 ( R 1 : dimethylamine & R 2 : propylamine), and B1 ( R 1 : ethylamine & R 2 : ethylamine) showed mild antimalarial activity which corresponds to the previous research work in PABA substituted pyrimidine derivatives (Choudhury et al, 2022). In aromatic amine containing compounds, B4 with R 1 : ethylamine & R 2 : m‐toluidine showed high antimalarial activity in both strains but compounds A3 ( R 2 : benzylamine), A4 ( R 2 : m‐F aniline), and A5 ( R 2 : p‐F aniline) with R 1 as dimethyl amine showed moderate inhibition.…”

Section: Resultssupporting

confidence: 86%

“…propylamine), and B1 (R 1 : ethylamine & R 2 : ethylamine) showed mild antimalarial activity which corresponds to the previous research work in PABA substituted pyrimidine derivatives (Choudhury et al, 2022). In aromatic amine containing compounds, B4 with R 1 : ethylamine & R 2 : mtoluidine showed high antimalarial activity in both strains but compounds A3 (R 2 : benzylamine), A4 (R 2 : m-F aniline), and A5 (R 2 : p-F aniline) with R 1 as dimethyl amine showed moderate inhibition.…”

Section: Structure-activity Relationship (Sar)supporting

confidence: 87%

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Hybrid PABA‐glutamic acid conjugated 1,3,5‐triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme

Choudhury,

Vinayagam,

Adhikari

et al. 2023

Chem Biol Drug Des

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Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first‐line treatments. Also because of the disruption in malaria prevention services during the COVID‐19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5‐triazine hybrids conjugated with PABA‐glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine‐sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non‐cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

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Section: Resultssupporting

confidence: 86%

Section: Structure-activity Relationship (Sar)supporting

confidence: 87%

Hybrid PABA‐glutamic acid conjugated 1,3,5‐triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme

Choudhury,

Vinayagam,

Adhikari

et al. 2023

Chem Biol Drug Des

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“…The Pf-DHFR inhibitors were developed using PABA and substituted aminopyrmidine. In silico screened compounds were also synthesized via the microwave assistance method [67]. The design and synthesis of aminobenzoic acid derivatives was achieved by reacting 4-amino benzoic acid and hydrochloride and refluxing [68].…”

Section: Synthesis Of Antimicrobial Agentsmentioning

confidence: 99%

Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications

Haroon,

Farwa,

Arif

et al. 2023

Biomedicines

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A “building block” is a key component that plays a substantial and critical function in the pharmaceutical research and development industry. Given its structural versatility and ability to undergo substitutions at both the amino and carboxyl groups, para-aminobenzoic acid (PABA) is a commonly used building block in pharmaceuticals. Therefore, it is great for the development of a wide range of novel molecules with potential medical applications. Anticancer, anti-Alzheimer’s, antibacterial, antiviral, antioxidant, and anti-inflammatory properties have been observed in PABA compounds, suggesting their potential as therapeutic agents in future clinical trials. PABA-based therapeutic chemicals as molecular targets and their usage in biological processes are the primary focus of this review study. PABA’s unique features make it a strong candidate for inclusion in a massive chemical database of molecules having drug-like effects. Based on the current literature, further investigation is needed to evaluate the safety and efficacy of PABA derivatives in clinical investigations and better understand the specific mechanism of action revealed by these compounds.

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“…The mechanistic basis of the antiprotozoal action of these active principals revealed the inhibition of a number of enzymes, such as dihydrofolate reductase (a reported target of anticancer drugs [19,20], which are crucial for the survival and virulence of Plasmodium [21], Leishmania, and Trypanosoma [22,23] species. In fact, dihydrofolate reductase aids in the replication of several microorganisms by reducing dihydrofolate to tetrahydrofolate for DNA synthesis [24,25]. Furthermore, the two antimalarial drugs, cycloguanil and pyrimethamine, as well as a codified antimalarial compound (P218), were also found to inhibit the DHFR enzyme [26].…”

Section: Introductionmentioning

confidence: 99%

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Dize,

Tali,

Ngansop

et al. 2024

Future Pharmacology

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Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.

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Microwave synthesis and antimalarial screening of novel 4-amino benzoic acid (PABA)-substituted pyrimidine derivatives as Plasmodium falciparum dihydrofolate reductase inhibitors

Cited by 8 publications

References 34 publications

Hybrid PABA‐glutamic acid conjugated 1,3,5‐triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme

Hybrid PABA‐glutamic acid conjugated 1,3,5‐triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme

Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

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