Synthesis, anti-varicella-zoster virus and anti-cytomegalovirus activity of quinazoline-2,4-diones containing isoxazolidine and phosphonate substructures

Abstract

Cycloadditions of N-substituted C-(diethoxyphosphoryl)nitrones to N-allylated quinazoline-2,4-diones functionalized at N3 with substituted benzoyl or benzyl groups proceeded with moderate to good diastereoselectivities (d.e. 28-68%). The synthesized isoxazolidine phosphonates were assessed for the antiviral activity against a broad range of DNA and RNA viruses. Compounds trans-13c, cis-13c/trans-13c (86:14), cis-15b/trans-15b (87:13) and trans-15d/cis-15d (95:5) exhibited the highest activity toward both TK and TK VZV strains (mean EC values in the range of 3.0-8.7 μM). The EC's for isoxazolidines trans-12a, cis-12a, cis-13a, trans-13d, cis-15a/trans-15a (50:50) ranged between 6.9 and 8.5 μM for VZV TK strain and between 10.7 and 13.2 μM for VZV TK strain. The isoxazolidine phosphonates cis-15/trans-15 having benzyl substituents both at N3 of the quinazoline-2,4-dione skeleton and at N2 of the isoxazolidine ring displayed some anti-cytomegalovirus potency but at the same time showed significant cytostatic activity for human embryonic lung fibroblasts (used to carry out the antiviral assays) as well as for other cell lines (i.e. CEM, L1210, HeLa and HMEC-1).

Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3‐Triazole Nucleosides

“…The standard benzoylation of N 1 ‐propargylquinazoline‐2,4‐dione 29 with benzoyl chlorides in the presence of triethylamine led to the formation of N 3 ‐benzoylated N 1 ‐propargylquinazoline‐2,4‐diones 30a − d in moderate to good yields without formation of by‐products. At first, attempts at benzylation of N 1 ‐propargylquinazoline‐2,4‐dione 29 following the strategy previously described for the synthesis of N 1 ‐allylated N 3 ‐benzoylquinazoline‐2,4‐dione were undertaken. Treatment of 29 with benzyl bromide in the presence of potassium hydroxide at 105°C for 4 h or 60°C for 48 h led to the formation of ca.…”

“…Based on the previous observations on analogous heterocyclic conjugates 24 – 26 synthesized in our research group (Fig. ) , functionalized benzyl and benzoyl groups were carefully selected as suitable substituents to be attached at C3 in the quinazolinone‐2,4‐dione framework. The synthetic strategy for our new series 1,2,3‐triazolenucleosides is presented in Scheme .…”

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“…Incorporation of electron-withdrawing groups such as NO 2 , CN, and F at para position of alkyl group can improve the activity against vaccinia virus. [24,25] Anti-HCMV activity is shown by 4-anilino substituted quinazoline compound (16,17) and which can be evaluated by performing inhibition studies of viral kinase pUL97 which is considered as target for antiviral activity. Thus, inhibition of viral protein is the mode of action shown by 4-anilino substituted quinazolines.…”

Discovery of 6‐Arylurea‐2‐arylbenzoxazole and 6‐Arylurea‐2‐arylbenzimidazole Derivatives as Angiogenesis Inhibitors: Design, Synthesis and in vitro Biological Evaluation

“…[27][28][29][30][31][32] Many of their derivatives are used for their anticancer, [33][34][35][36][37] antiviral, [38][39][40][41][42] antifungal, [43][44][45][46] antimicrobial, [47][48][49][50] anti-inflammatory, [51][52][53][54] analgesic, [55][56][57] andi mmunotropic [58][59][60] activities. [27][28][29][30][31][32] Many of their derivatives are used for their anticancer, [33][34][35][36][37] antiviral, [38][39][40][41][42] antifungal, …”

“…Benzoxazoles and benzimidazoles are ah ighly significant group of biological molecules that are widely found in agrochemicals, pharmaceuticals, synthetic drugs, and bioactive natural products. [27][28][29][30][31][32] Many of their derivatives are used for their anticancer, [33][34][35][36][37] antiviral, [38][39][40][41][42] antifungal, [43][44][45][46] antimicrobial, [47][48][49][50] anti-inflammatory, [51][52][53][54] analgesic, [55][56][57] andi mmunotropic [58][59][60] activities. Recently,6-substituted benzoxazole or benzimidazole derivatives have been developed as multi-kinasei nhibitors, including tyrosine and serine/threonine kinases.…”