Improved Flavodoxin Inhibitors with Potential Therapeutic Effects against Helicobacter pylori Infection

Abstract

Helicobacter pylori (Hp) infection affects one-half of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.

QSAR Models for Prediction of Binding and Inhibitory Properties of [(E)-2- R-vinyl]benzene Derivatives with Therapeutic Effects against Helicobacter pylori

“…Four Hp flavodoxin inhibitors were identified in previous work [19] and subsequently optimized [20]. Three of them, originally named C1, C2 and C4, were shown to display bactericidal activity against Hp.…”

“…In this work, those two compounds are referred to as I and II to retain their initial numbering. Twenty two additional compounds: 7 and 15 analogues of I and II respectively, were selected from [20]. The numbering assigned to them in that work [20] is retained here for clarity (Table 1).…”

“…Twenty two additional compounds: 7 and 15 analogues of I and II respectively, were selected from [20]. The numbering assigned to them in that work [20] is retained here for clarity (Table 1). Compounds I, II, plus the additional 22 compounds constitute the database that we have used for the development of the QSAR models.…”

“…As described elsewhere [20], the biological response variables (BR) tested for each compound were: affinity (K d ) of the compound/Hp-Fld complex, minimal inhibitory concentration (MIC), minimal cytotoxic concentration (MCC), and therapeutic index (TI=MCC/MIC). Normality for each BR (i.e., the fit to a Normal statistical distribution) was checked and, in cases where it was not met, some compounds were removed to obtain a dataset with Normal distribution.…”

“…No new drugs have been developed in recent years to treat Hp infection, but some selective targets (one of them being the protein flavodoxin: Hp-Fld) have been identified [16]. Hp-Fld is an electron carrier essential for Hp viability [17,18] and it has been used in previous works [19,20] as target for the discovery of novel compounds that could be potential drugs against Hp. Four different biological responses (BR) or biological activities were assayed for those novel compounds, which are mainly derived from a common substructure represented in Figure 1.…”