Wang resin catalysed sonochemical synthesis of pyrazolo[4,3-d]pyrimidinones and 2,3-dihydroquinazolin-4(1H)-ones: Identification of chorismate mutase inhibitors having effects on Mycobacterium tuberculosis cell viability

• Published in: Bioorganic chemistry 2023-05, Vol.134, p.106452-106452, Article 106452
• Main Authors: Shukla, Sharda, Nishanth Rao, R., Bhuktar, Harshavardhan, Edwin, Rebecca Kristina, Jamma, Trinath, Medishetti, Raghavender, Banerjee, Sharmistha, Giliyaru, Varadaraj Bhat, Shenoy, Gautham G., Oruganti, Srinivas, Misra, Parimal, Pal, Manojit
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival; Chorismate Mutase; Mammals - metabolism; Molecular Structure; Mycobacterium tuberculosis; N-heteroarenes; Pyrimidinones - chemistry; Structure-Activity Relationship; Wang resin; Zebrafish - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106452

The synthesis, in silico and in vitro evaluation of 5,5-disubstituted pyrazolo[4,3-d]pyrimidinones and 2,2-disibstituted 2,3-dihydroquinazolin-4(1H)-ones furnished the first example of MtbCM inhibitors that showed effects on Mtb cell viability in infected macrophages. [Display omitted] •Pyrazolopyrimidinones and quinazolinones were explored as inhibitors of CM.•These compunds were accessed via a Wang resin catalysed sonochemical method.•Among them, 3b and 3c interacted with and inhibited MtbCM in silico and in vitro.•They decreased the Mtb cell viability without affecting mammalian cells significantly.•Being first example of CM inhibitors to show such effects they are of further interest. The enzyme chorismate mutase (or CM that is vital for the survival of bacteria) is an interesting pharmacological target for the identification of new anti-tubercular agents. The 5,5-disibstituted pyrazolo[4,3-d]pyrimidinone derivatives containing the fragment based on 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide were designed and explored as the potential inhibitors of chorismate mutase. Based on encouraging docking results of two representative molecules evaluated in silico against MtbCM (PDB: 2FP2) the Wang resin catalysed sonochemical synthesis of target N-heteroarenes were undertaken. The methodology involved the reaction of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with the appropriate cyclic/acyclic ketones to afford the desired products in acceptable (51–94%) yields. The methodology was also extended successfully towards the synthesis of 2,2-disubstituted 2,3-dihydroquinazolin-4(1H)-ones in excellent (85–90%) yields. In vitro MTT assay against the RAW 264.7 cell line followed by enzymatic assay against MtbCM identified 3b and 3c as active compounds that showed two H-bonding via their NH (at position 6) and CO group with MtbCM in silico and encouraging (54–57%) inhibition at 30 µM in vitro. Notably, none of the 2,2-disubstituted 2,3-dihydroquinazolin-4(1H)-ones showed any significant inhibition of MtbCM suggesting the favourable role of the pyrazole moiety in case of pyrazolo[4,3-d]pyrimidinones. The favourable role of cyclopentyl ring attached to the pyrazolo[4,3-d]pyrimidinone moiety and that of two methyl groups in place of cyclopentyl ring was also indicated by the SAR study. Besides showing effects against MtbCM in the concentration response study, 3b and 3c showed little or no effects on mammalian cell viability up to 100 µM in an MTT assay b