Design and Synthesis of Diaminotriazines as Anti-Tuberculosis DHFR Inhibitors

Abstract

A series of novel 2,4 diamino-s-triazine was designed as potential Mycobacterium tuberculosis (Mtb) Dihydro folate reductase inhibitors. The synthesized compounds were evaluated in whole cells by employing Resazurin Microtitre Plate Assay (REMA) against Mtb H 37 Rv, using known DHFR inhibitors Methotrexate and Trimethoprim as standard drugs. The most active compound in the whole cell assay was selected for DHFR enzyme assay against the pathogen and human enzymes. The enzyme assay results revealed that this compound is a selective pathogenic DHFR inhibitor, with 13 fold more selectivity than Methotrexate. Thus, these derivatives have provided promising selective Hits/Leads as MTb DHFR inhibitors and can provide valuable information for further design of potent anti-TB drugs.

Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors

“…Researchers have identified nitrogen heterocycles, − boron containing carboranes, and a tripeptide as Mtb DHFR inhibitors . Our research group has been actively involved in the search of DHFR inhibitors and has synthesized several novel, diverse inhibitors of DHFR for Mtb , and opportunistic pathogens, − including Mycobacterium avium . , Additionally, we have isolated Mtb DHFR enzyme from recombinant Saccharomyces cerevisiae strains and purified it using affinity chromatography with a novel epoxy bound resin linked to the inhibitor, methotrexate. , …”

“…10 Our research group has been actively involved in the search of DHFR inhibitors and has synthesized several novel, diverse inhibitors of DHFR for Mtb 11,12 and opportunistic pathogens, 13−15 including Mycobacterium avium.…”

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“…10 Our research group has been actively involved in the synthesis of several novel, diverse inhibitors of DHFR for Mtb 11,12 and opportunistic pathogens, [13][14][15] including Mycobacterium avium. 16,17 Additionally, we have isolated Mtb DHFR enzyme from recombinant Saccharomycescerevisiae strains and purified it using a novel affinity column.…”

Potenciais inibidores de di-idrofolato redutase de>i< Mycobacterium tuberculosis>/i< (>i<MtDHFR>/i<): >i<Docking>/i< molecular, síntese e avaliação enzimática de derivados dos ácidos aminobenzóico e >i<p>/i<-aminocinâmico

“…A transformação do ácido di-idrofólico em ácido tetraidrofólico ocorre por ação da DHFR tornando-se uma etapa chave na formação da timidina que será utilizada para síntese de DNA. Caso exista a inibição da enzima, o fornecimento de timidina no ciclo da síntese não ocorrerá, ocasionando então a parada do ciclocelular ou inibição da sua replicação (Lele et al, 2015;Lele et al, 2016). A DHFR é formada por uma folha beta central de sete fitas cercada por quatro hélices alfa (Li et al, 2000;Hong et al, 2015;Riyadh et al, 2018;Tawari et al, 2011) e uma única fita C-terminal antiparalela.…”

“…Sendo assim, as diferenças nos resíduos de aminoácidos essenciais para a ação do sítio catalítico e o acesso ao bolsão com afinidade pelo GOL poderão servir como base para estratégias interessantes na obtenção de prováveis inibidores seletivos de MtDHFR (Figura 4E). apresentando em sua estrutura grupos semelhantes ao MTX e à TMP (Li et al, 2000;El-Hamamsy et al, 2007;Tawari et al, 2015;Lele et al, 2015;Lele et al, 2016) Lele et al, 2015;Lele et al, 2016). Derivados do 1,3,5-triazaspiro [5.5] (Kronenberger et al, 2020).…”