Synthesis and biological activity of sulfur compounds showing structural analogy with combretastatin A-4

Abstract

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15).

Recent Developments in Drug Discovery for Leishmaniasis and Human African Trypanosomiasis

“…Examples include the protoberberine natural product palmatine, active against L. infantum , 154 and the quinonemethide natural products maytenin ( 31 ) and pristimerin ( 32 ) (Figure 4 ), with demonstrated activity against L. chagasi . 155 Screens employing L. donovani promastigotes are also prevalent and have identified a wide range of promising antileishmanial natural products (EC 50 < 1 μg/mL) from the plants Plumbago zeylanica , 156 Septoria pistaciarum , 157 Abrus schimperi , 158 Prosopis glandulosa var. glandulosa , 159 Clerodendrum eriophyllum , 160 and Uvaria grandiflora .…”

“…Numerous natural products have also been reported to successfully affect in vitro those Leishmania parasites that are the causative agents of visceral leishmaniasis. Examples include the protoberberine natural product palmatine, active against L. infantum , and the quinonemethide natural products maytenin ( 31 ) and pristimerin ( 32 ) (Figure ), with demonstrated activity against L. chagasi . Screens employing L. donovani promastigotes are also prevalent and have identified a wide range of promising antileishmanial natural products (EC 50 < 1 μg/mL) from the plants Plumbago zeylanica , Septoria pistaciarum , Abrus schimperi , Prosopis glandulosa var.…”

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity

“…11 In other work by our research group, we explored the effect of changing the attachment position of the sulfur atom to ring A, and we found that this modification led to a major loss in activity. 12 …”