Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents

Abstract

KEYWORDSIn the reaction of 2-amino-3-carbethoxythiophene derivative 2b with hydrazine hydrate the respective aminocarbohydrazide 3 was isolated. Treatment of the latter product with carbon disulfide in alkaline medium caused a heterocyclization to give 1,3,4-oxadiazole-2-thione 5 rather than 3-amino-2-thioxothieno[2,3-d]pyrimidin-4-one 4, which could be obtained on treatment of carbohydrazide 3 with thiourea. The structure of products 4 and 5 was proved by spectroscopic methods and chemical transformations. Derivatization led to two novel series of condensed and uncondensed thiophenes, which were of significant interest for biological study. Since compound 4 contains two adjacent reactive functional groups, it reacted readily with different electrophilic reagents to provide a series of thieno[2,3-d]pyrimidin-4-one derivatives with annelated bridgehead nitrogen heterocycles 8-11, whereas a second series of 3-heteroaryl-substituted thiophenes 13-17 was obtained by thioamide functionalization in 1,3,4-oxadiazole derivative 5 using various chemical reagents. The new thiophene-based derivatives were evaluated for their preliminary antimicrobial activity against a representative panel of Gram-positive and Gram-negative bacteria as well as fungi strains. The compounds tested displayed different levels of inhibitory effects, with the assays carried out on two pathogenic bacteria and two pathogenic fungi. Of these compounds, the monocyclic aminothiophene derivative 15 showed the highest effect on pathogenic bacteria, while the tricyclic condensed thiophene derivative 8 was observed to have the same inhibitory effect against pathogenic mould (Aspergillus flavus) as the reference drug Amphotericin B. For those derivatives belonging to first series of condensed thiophenes with annelated bridgehead nitrogen heterocycles, it has been observed that the antibacterial effect was in general found to be significantly higher than the corresponding uncondensed analogues. Although most of the condensed and uncondensed thiophenes under investigation showed generally remarkable in vitro antibacterial activity, unfortunately, no significant antifungal activity was observed with any of the compounds tested except for 8. Surprisingly, compound 8 displayed an excellent effect on fungus (A. flavus) on the one hand, whereas the lowest effect on bacteria on the other. The attachment of a triazolothiadiazine moiety to a thiophene ring could be considered as a promising strategy for the development of new therapeutic antibacterial agents related to the aminothiophene system. Thienopyrimidinone Cyclocondensation Cyclodesulfurization Hydrazinolysis Alkylation Antimicrobial activity

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses

“…The thiophene ring is present in numerous pharmacologically important compounds and natural products [1,2,3,4,5,6,7]. Highly substituted thiophenes have been synthesized by various methodologies and examined for diverse pharmacological activities [8,9,10,11,12]. These include the antiallergic agent methaphenilene, the anticonvulsant tiagabine, and biotin which is used for preventing and treating biotin deficiency associated with pregnancy (Figure 1).…”

Expeditious Scalable Catalyst-Free One-Pot Synthesis of 4-Alkoxy-5-amino-3-methylthiophene-2-carbonitriles via Sequential Reactions­ of Lithiated Alkoxyallenes with Isothiocyanates and 2-Bromoacetonitrile

“…IR (neat): 3330, 3116, 3052, 2935IR (neat): 3330, 3116, 3052, , 2877IR (neat): 3330, 3116, 3052, , 2192IR (neat): 3330, 3116, 3052, (C≡N), 1620IR (neat): 3330, 3116, 3052, , 1565IR (neat): 3330, 3116, 3052, , 1498IR (neat): 3330, 3116, 3052, , 1460IR (neat): 3330, 3116, 3052, , 1410IR (neat): 3330, 3116, 3052, , 1348IR (neat): 3330, 3116, 3052, , 1321IR (neat): 3330, 3116, 3052, , 1272IR (neat): 3330, 3116, 3052, , 1243IR (neat): 3330, 3116, 3052, , 1195IR (neat): 3330, 3116, 3052, , 1128IR (neat): 3330, 3116, 3052, , 1106IR (neat): 3330, 3116, 3052, , 1088IR (neat): 3330, 3116, 3052, , 1022 The 1 H-13 C HMBC and 1 H-13 C HSQC 2D experiments provided additional support for the proposed structure. 13), 181 (25), 180 (16), 179 (85), 166 (11), 165 (16), 154 (9), 153 (44), 152 (100), 140 (14, 138 28), 126 (10), 125 (21), 124 (18, 120 (8), 112 (7), 110 (9), 99 (10), 98 (6), 97 (36), 96 (11), 86 (18), 75 (7), 73 (15), 72 (30), 71 (11), 70 (29), 69 (7), 66 (18), 65 (10), 64 (12), 60 (13), 59 (22), 58 (92), 57 (20), 54 (15), 53 (8), 52 (7), 45 (74), 44 (12), 43 (28), 42 (34), 41 (15), 39 (19), 38 (8).…”

“…4,7 Manifold of synthetic and practically useful properties of thiophenes bearing alkoxy, 8 amino, 9 and cyano 10 groups maintain a continuously growing interest to their new representatives. For instance, a variety of dyes, 11 agrochemicals, 12 and pharmaceuticals 13 often use a 2-aminothiophene motif in its skeletal backbone. In addition, 2-aminothiophene derivatives exhibit a diverse set of therapeutic activities, for example, anti-inflammatory, 14 anticonvulsant, 15 antimicrobial, 16 antifungal, 17 antioxidant, 18 and other activities.…”

“…13 C NMR (100 MHz, CDCl 3 ): δ = 13.2 (CH 3 ), 33.6 (NCH 3 ), 68.4 (C 5 H 5 , Fc), 69.3 (β-C, Fc), 69.6 (α-C, Fc), 71.8 (OCH 2 Fc), 81.8 (i-C, Fc), 83.2 (2-C), 116.7 (CN), 133.9 (4-C), 144.1 (3-C), 150.6 (5-C). N. A. Nedolya et al Paper Syn thesis MS (EI): m/z (%) = 366 (1, [M] + ), 200(18), 199 (100), 197 (8), 121 (47), 56(13), 42 (6).Anal. Calcd for C 18 H 18FeN 2 OS (366.3): C, 59.03; H, 4.95; N, 7.65; S, 8.75.…”

“…15 N NMR (40 MHz, CDCl 3 ): δ = -301.0. MS (EI, 70 eV): m/z (%) = 237 (5, [M + 1] + ), 236 (23, [M] + ), 221 (24), 154(7), 153 (100), 126 (10), 70 (6), 69 (26), 67 (6), 41 (47), 39(13).…”