Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

Abstract

Bacterial infections have increased dramatically in recent years. Bacteria have been the cause of some of the most deadly diseases and widespread epidemics in human civilization.1) Moreover, the widespread use and misuse of antibiotics has caused bacterial resistance. Some of these resistant strains, such as vancomycin-resistant enterococci (VRE) and multidrug resistant Staphylococcus aureus (MRSA), are capable of surviving the effects of most, if not all, antibiotics currently in use. [2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria. 14)Thiadiazoles belong to the wider category of imidazole and triazole synthetic antifungal drugs which are designed to inhibit the enzyme cytochrome P450 14a-demethylase and inhibit the conversion of lanosterol to ergosterol, which is required in fungal cell membrane synthesis.1,3,4-Thiadiazoles are known to possess antibacterial and antifungal properties similar to those of well known sulphonamide drugs.15) Thus, the 1,3,4-thiadiazoles exhibit a broad spectrum of biological activities possibly due to the presence of the toxophoric -N-C-S moiety.16) Prompted by these observations and in continuation of our search for bioactive molecules, we designed the synthesis of a series of novel sulfonamide-1,3,4-thiadiazoles, emphasizing, in particular, on the strategy of combining two chemically different but pharmacologically compatible molecules (the sulfonamide nucleus and the five member heterocycle) in one frame, in order to study their antibacterial and antifungal activities.Chemistry The synthetic pathway followed for the preparation of the title compounds was accomplished as shown in Chart 1.Starting from ethyl(2-chlorosulfonyl-4,5-dimethoxyphenyl)acetate (1) 17,18) by reaction with secondary aliphatic amines in anhydrous benzene the corresponding sulfonamides Results and DiscussionBiological Evaluation and Lipophilicity Studies The results of antibacterial and antifungal activity of compounds 5a-m against a panel of selected Gram positive, Gram negative bacteria and fungi are presented in Tables 1 and 2 in comparison with those of the reference drugs ampicillin and streptomycin, bifonazole and ketoconazole respectively.Results of antibacterial activity of compounds (Table 1) show that the minimum inhibitory concentration (MIC) of compounds varies in the range of 0.92-4.6ϫ10 Ϫ2 mmol/ml, while minimum bactericidal concentration (MBC) varies between 1. 75-9.20ϫ10 Ϫ2 mmol/ml. Compounds 5a, 5b, 5c and 5g showed the lowest antibacterial activity among the tested compounds with 5a being t...

Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation

“…Our design supported from our previous findings [10][11][12][13][14][15] addressed the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole [16][17][18][19][20][21][22][23][24][25][26] and a chalcone, [27][28][29] to yield a class of compounds with interesting antimicrobial properties…”

“…The last two species are in general more sensitive than others used in experiment. 11,14 No correlation of antimicrobial activity, and lipophilicity, calculated as C log P, was observed.…”

1,3,4-Thiadiazole and 1,2,4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

“…In spite of the development of new drugs, such as new azole or echinocandin derivatives, there has been a dramatic increase in both anti-Candida resistance and the frequency of invasive Candida infections (Pfaller, 2012). Among enormous classes of heterocyclic compounds, the synthesis of new derivatives of 1,2,4-triazole-3-thiones and 2-amino-1,3,4-thiadiazoles has been attracting considerable attention because of their broad biological activity, including antibacterial and antifungal (Güzeldemirci, Küçükbasmaci, 2010;Plec et al, 2011;Camoutsis et al, 2010;Küçükgüzel et al, 2007;Kadi et al, 2007), anti-tubercular (Küçükgüzel et al, 2001;Küçükgüzel et al, 2008), antiviral (Abdel-Aal et al, 2003;Küçükgüzel et al, 2008), antioxidant (Ayhan-Kilcigil et al, 2004;Khan et al, 2010), antitumoral Rzeski, Matysiak, Kandefer-Szerszen, 2007;Mavrova et al, 2009), anti-inflammatory (Amir, Shikha, 2004;Kadi et al, 2007;Küçükgüzel et al, 2007;Kumar et al, 2008), and anticonvulsant activity (Kane et al, 1994;Sharma et al, 2011;Dogan et al, 2002). Clinically-used antifungal azole drugs containing either an imidazole (e.g., econazole, miconazole, clotrimazole, and ketoconazole) or a 1,2,4-triazole moiety (e.g., fluconazole and itraconazole) have a high therapeutic index and significant safety profile (Wang et al, 2009).…”

Synthesis, Characterization and Antimicrobial Screening of Sulphonamide Based 1, 3, 4-Oxadiazoles

“…In the present program, our aim is to synthesize new molecules containing multiple heterocyclic systems and to study their characterization as well as their activities. In continuation to our previous work [24] and because of the medicinal importance of sulphonamide and 1,3,4-oxadiazole as a core moiety, we report herein the synthesis of a new class of 2-((5-aryl-1,3,4-oxadiazol-2-yl)thio)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)acetamide (VI [1][2][3][4][5][6][7][8][9][10][11][12][13][14] ) and try to develop potential antimicrobials. The structures of newly synthesized compounds were elucidated on the basis of infrared (IR), 1 H NMR, 13 C NMR, and mass spectral analysis.…”

“…The sulphonamide scaffold is a useful structural motif for displaying chemical functionality in biologically active molecules.Several drugs containing sulfonamide functionality are in clinical use which includes antifungal and antibacterial drugs [1],carbonic anhydrase inhibitors [2],anti-inflammatory agents [3],anticonvulsant agents [4],antimalarial agents [5],protease inhibitors [6], hypertension agent [7], and cytotoxic agent [8]. They are also found to have wide applications in anti-cancer agent [9].…”