Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase, GuaB2, inhibitors

Sahu, Niteshkumar U.; Singh, Vinayak; Ferraris, Davide M.; Rizzi, Menico; Kharkar, Prashant S.

doi:10.1016/j.bmcl.2018.04.045

Cited by 25 publications

(27 citation statements)

References 18 publications

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“…Furthermore, 3‐hydroxy‐2‐substituted aryl flavones ( 13a‐h ) were subjected to O ‐alkylation with 15a‐c in the presence of anhydrous K 2 CO 3 /dry DMF to yield the NCEs ( 16a‐h , Table ). Synthesis of 1,2,3‐triazole derivatives was proceeded in two steps as described previously (Schemes ) (Sahu et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of substituted 1,2,3‐triazole derivatives 24/25/26a‐c was carried out according to the previously reported work on Mtb GuaB2 inhibitor development. (Sahu et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…In an interesting study, Cryptosporidium parvum IMPDH ( Cp IMPDH) inhibitors were screened against several bacterial pathogens, generating lead molecules that could be further optimized (Shah & Kharkar, ). All reported Cp IMPDH inhibitors have common pharmacophoric features—two aromatic rings separated by a linker (Figure ) (Sahu, Singh, Ferraris, Rizzi, & Kharkar, ). Screening of these molecules against Hp IMPDH led to the identification of C91 ( 9 , Figure ), the most potent Hp IMPDH inhibitor, belonging to 1 H ‐benzimidazole series with IC 50 = 8 and 1.1 nM for Cp IMPDH and Hp IMPDH, respectively (Gollapalli et al, ; Hedstrom et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous work on Mycobacterium tuberculosis ( Mtb ) IMPDH, GuaB2, inhibitor development (Sahu et al, ) was the main motivation for us to venture into this new territory where only few groups are working across the globe. Interestingly, the sequence identity between Mtb GuaB2 and Hp IMPDH was observed to be 55.77% (Table S1, Supporting Information).…”

Section: Introductionmentioning

confidence: 99%

“…With reference to microbial IMPDH inhibitors, Cp IMPDH (Maurya et al, ) and Mtb GuaB2 (Sahu et al, ) inhibitors have been reported to contain 1,2,3‐triazole core structure. Our previous in vitro screening campaign against Mtb GuaB2 led to the identification of 1,2,3‐triazole containing hits ( 24a , 24b , and 26a , Table ) (Sahu et al, ) active in Mtb whole‐cell (MIC 90 = 50 μM) and biochemical assays for Mtb GuaB2 inhibition ( 24a , 35% and 26a , 52.24% inhibition, at 50 μM) (Sahu et al, ). In this study, by learning from our previous stint with microbial IMPDH inhibitor development, we report the design, synthesis, and biological evaluation of Hp IMPDH inhibitors belonging to flavone (Series 1) and 1,2,3‐triazole (Series 2) chemotypes.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase (HpIMPDH) inhibitors

Sahu

Purushothaman

Thiruvenkatam

et al. 2018

Drug Development Research

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Inosine 5′‐monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3‐triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9–99.9% and 16–57%, respectively, at 10 μM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 μM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…Synthesis of substituted 1,2,3‐triazole derivatives 24/25/26a‐c was carried out according to the previously reported work on Mtb GuaB2 inhibitor development. (Sahu et al, ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase (HpIMPDH) inhibitors

Sahu

Purushothaman

Thiruvenkatam

et al. 2018

Drug Development Research

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Development, synthesis, and biological evaluation of sulfonyl‐α‐l‐amino acids as potential anti‐Helicobacter pylori and IMPDH inhibitors

Galal

Mohamed

Abdel‐Aziz

et al. 2021

Archiv der Pharmazie

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Inosine 5ʹ-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of DNA and RNA, and it has been exploited as a promising target for antimicrobial therapy. The present study discusses the development and synthesis of a series of sulfonyl-α-L-amino acids coupled with the anisamide scaffold and evaluates their activities as anti-Helicobacter pylori and IMPDH inhibitors. Twenty derivatives were synthesized and their structures were established by highresolution mass spectrometry and 1 H and 13 C nuclear magnetic resonance measurements. Four compounds (6, 10, 11, and 21) were found to be the most potent and selective molecules in the series with minimum inhibitory concentration (MIC) values <17 µM, which were selected to test their inhibitory activities against HpIMPDH and human (h)IMPDH2 enzymes. In all tests, amoxicillin and clarithromycin were used as reference drugs. Compounds 6 and 10 were found to have a promising activity against the HpIMPDH enzyme, with IC 50 = 2.42 and 2.56 µM, respectively. Moreover, the four compounds were found to be less active and safer against hIMPDH2 than the reference drugs, with IC 50 > 17.17 µM, which makes sure that their selectivity is toward HpIMPDH and reverse to that of amoxicillin and clarithromycin. Also, the synergistic antibacterial activity of compounds 6, 10, amoxicillin, and clarithromycin was investigated in vitro. The combination of amoxicillin/compound 6 (2:1 by weight) exhibited a significant antibacterial activity against H. pylori, with MIC = 0.12 µg/ml. The molecular docking study and ADMET analysis of the most active compounds were used to elucidate the mode-of-action mechanism.

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Application of NMI-TfCl-mediated amide bond formation in the synthesis of biologically relevant oxadiazole derivatives employing less basic (hetero)aryl amines

et al. 2021

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Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase, GuaB2, inhibitors

Cited by 25 publications

References 18 publications

Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase (HpIMPDH) inhibitors

Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase (HpIMPDH) inhibitors

Development, synthesis, and biological evaluation of sulfonyl‐α‐l‐amino acids as potential anti‐Helicobacter pylori and IMPDH inhibitors

Application of NMI-TfCl-mediated amide bond formation in the synthesis of biologically relevant oxadiazole derivatives employing less basic (hetero)aryl amines

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