Synthesis of N-Substituted 5-Iodouracils as Antimicrobial and Anticancer Agents

Abstract

This study reports the synthesis of some substituted 5-iodouracils and their bioactivities. Alkylation of 5-iodouracils gave predominately N1-substituted-(R)-5-iodouracil compounds 7a-d (R = n-C4H9, s-C4H9, CH2C6H11, CH2C6H5) together with N1,N3-disubstituted (R) analogs 8a-b (R = n-C4H9, CH2C6H11). Their antimicrobial activity was tested against 27 strains of microorganisms using the agar dilution method. The analogs 7a, 7c and 7d displayed 25-50% inhibition against Branhamella catarrhalis, Neisseria mucosa and Streptococcus pyogenes at 0.128 mg/mL. No antimalarial activity was detected for any of the analogs when tested against Plasmodium falciparum (T9.94). Their anticancer activity was also examined. Cyclohexylmethyl analogs 7c and 8b inhibited the growth of HepG2 cells. Significantly, N1,N3-dicyclohexylmethyl analog 8b displayed the most potent anticancer activity, with an IC50 of 16.5 μg/mL. These 5-iodouracil analogs represent a new group of anticancer and antibacterial agents with potential for development for medicinal applications.

Биологическая Активность Адамантансодержащих Моно- И Полициклических Пиримидиновых Производных (Обзор)

“…I íàñòîÿùåãî îáçîðà [1] èçëîaeåíû ìàòåðèàëû, ñâÿçàííûå ñ ñèíòåçîì àäàìàíòàíñîäåðaeàùèõ ïèðèìèäèíîâûõ ïðîèçâîäíûõ. ** Ïðè èçëîaeåíèè äàííûõ áèîëîãè÷åñêèõ èññëåäîâàíèé àâòîðàìè ðàáîò áûëè èñïîëüçîâàíû ñëåäóþùèå ïîêàçàòåëè [ïðèâîäèòñÿ àááðåâèàòóðà è åå ðàñøèôðîâêà (åñëè îíà èìååòñÿ), äàííàÿ â ñîîòâåòñòâóþùåé ïóáëèêàöèè]: MIC -ìèíèìàëüíàÿ èíãèáèðóþùàÿ êîíöåíòðàöèÿ [2,3,6]. MIC 50 -ìèíèìàëüíàÿ èíãèáèðóþùàÿ êîíöåíòðàöèÿ ïðåïàðàòà, ïîäàâëÿþùàÿ ðàçâèòèå âèðóñèíäóöèðîâàííîãî öèòîïàòè÷åñêîãî äåéñòâèÿ íà 50 % [23,51].…”

“…Àíàëîãè÷íûå õàðàêòåðèñòèêè äëÿ E.ñ. ñîñòàâëÿþò: íå àêòèâíî -14 -21. ðàáîòàõ [5,6] ïðèâîäÿòñÿ äàííûå î áèîëîãè÷åñêîé àêòèâíîñòè 2-RS-çàìåùåííûõ ïèðèìèäèí-4-îíîâ, â òîì ÷èñëå äâóõ 2-(1-àäàìàíòèëòèî)ïðîèçâîäíûõ 7à [5] è 7á [6]. Áûëà èçó÷åíà èõ àíòèìèêðîáíàÿ, àíòèìàëÿðèéíàÿ è öèòîòîêñè÷íàÿ àêòèâíîñòü.…”

“…Äëÿ ñî-åäèíåíèÿ 7á íàèâûñøàÿ àêòèâíîñòü â îòíîøåíèè B. catarrhalis ïðîÿâèëàñü ïðè MIC, ðàâíîé 32 ìêã/ìë. Ïðè 128 ìêã/ìë ïðåïàðàò áûë àêòèâåí â îòíîøåíèè S. pyogenes (25%) è N. mucosa (25 %) [6].Àíòèìàëÿðèéíàÿ àêòèâíîñòü. Àäàìàíòèëüíîå ïðîèçâîäíîå 7á ïðîÿâèëî âûñîêóþ àíòèïëàçìîäèàëüíóþ àê-òèâíîñòü â îòíîøåíèè óñòîé÷èâîãî ê õëîðîõèíó âîçáóäèòåëþ P. Falciparum (ïðèâîäèò ê òÿaeåëîé ôîðìå ìàëÿ-ðèè): IC 50 × 10 -6 < 10 -5 (M).…”

“…Âðåìÿ 50 % âûñâîáîaeäåíèÿ öèòîçèíà èç àëüãèíàò-ãåëåé, ñîäåðaeàùèõ ñîåäèíåíèå 9, â êèñëîé ñðåäå ñîñòàâëÿëî 4,5 ÷, òîãäà êàê àíàëîãè÷íàÿ õàðàêòåðèñòèêà ãåëåé, ñîäåð-aeàùèõ ðîäîíà÷àëüíûé öèòîçèí, ñîñòàâëÿëà 1,5 ÷. 7à [5] 32,0 35,0 32,5 36,91 7á [6] 5,0 > 50 > 50 11,35 à) Ãîðìîíîçàâèñèìûå êëåòêè ìîëî÷íîé aeåëåçû ìûøåé; á) íåâîñïðèèì÷èâûå ê ëåêàðñòâàì ë¸ãî÷íûå êëåòêè; â) êëåòêè êàðöèíîìû ïå÷åíè ÷åëîâåêà; ã) êëåòêè ëåéêåìèè ìûøåé.…”

Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

“…Freshly distilled diazomethane solution in ether (10 mL), generated from Diazald (3.0 g, 14.0 mmol), was added dropwise to a stirred solution of 78a 168 with spectroscopic data as described above. and Pd(OAc) 2 (1.6 mg, 0.007 mmol) were added to a stirring solution of 78a (46 mg, 0.14 mmol)…”