An Insight into Rational Drug Design: The Development of In-House Azole Compounds with Antimicrobial Activity

Abstract

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca.

Keywords: antimicrobial; azoles; heterocycles; organic synthesis; structure-activity relationship.

Scheme 9

The synthetic pathway for the antimicrobial thiazolyl-1,2,4-triazole Schiff bases [148,149]. Legend: EtOH—ethanol; rt—room temperature.

Figure 1

Structures of some of the currently FDA-approved azole drugs with antibacterial and antifungal activities.

Figure 2

The general structures of the antimicrobial aryl and hetaryl-1,3,4-oxadiazoline compounds. The additional aromatic or heteroaromatic structures grafted on the 1,3,4-oxadiazoline ring were: 4-chloro-phenoxymethyl (a), pyridyl (b), 7-oxy-chromenyl (c), 2,4-bisthiazoles (d), 2-acetylamino-thiazole (e), and 2-aryl-thiazole (f).

Scheme 1

The general synthetic route for the 4-acetyl-4,5-dihydro-1,3,4-oxadiazol-2-yl derivatives.

Figure 3

Structures of the chromenyl-acyl-hydrazones (1a–m) and chromenyl-1,3,4-oxadiazoline (2a–m) compounds.

Figure 4

Structures of the antimicrobial 2,4-bisthiazolyl-1,3,4-oxadiazoline (3a–i) and N-acetyl-thiazolyl-1,3,4-oxadiazoline (4a–i) compounds.

Figure 5

Structures of the antimicrobial 2-pyridyl-thiazolyl-1,3,4-oxadiazoline (6a–g) compounds and their acylhydrazones (5a–g).

Figure 6

The general structures of the antimicrobial aryl and hetaryl-1,3,4-thiadiazoline compounds. The additional aromatic or heteroaromatic structures grafted on the 1,3,4-thiadiazoline ring were: chromone moieties (a), substituted phenyl rings (b), and aryl-thiazoles (c).

Scheme 2

The general synthetic route for the 4-acetyl-4,5-dihydro-1,3,4-thiadiazol-2-yl derivatives. Legend: abs. = absolute; EtOH = ethanol; rt = room temperature; t = temperature; Py = pyridine.

Figure 7

Structures of the antimicrobial N-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-thiadiazol-2-yl)-acetamides (8a–h), N-(4-acetyl-5-(2-arylthiazol-4-yl)-4,5-dihydro-1,3,4-thiadiazol-2-yl) (8i–j), and their corresponding N¹-arylidene-thiosemicarbazones (7a–j).

Figure 8

The development of the antimicrobial oxadiazoline and thiadiazoline compounds. (-) means low or no activity against a strain, while (+) means activity against a strain. If the number of (+) increases, it means that the activity is better on certain strains. Similarly for the colors scheme: red means no or low activity, orange-yellow means low or moderate activity, while green means good to excellent activity.

Scheme 3

The general synthetic routes for the antimicrobial 1,3,4-thiadiazolyl-thioethers (9a–f, 10a–b, and 11a–e) and Schiff bases (12a–d, 13a–d, and 14a–b). Legend: EtOH = ethanol; AcOH = acetic acid; MW = microwave; W = watts; t = temperature.

Figure 9

SAR studies in the antimicrobial 1,3,4-thiadiazolyl-thioethers (9a–f, 10a–b, and 11a–e) and Schiff bases (12a–d, 13a–d, and 14a–b). (+) means activity against a strain. If the number of (+) increases, it means that the activity is better on certain strains. Similarly for the colors scheme (reffering to the heat bars): red means no or low activity, orange-yellow means low or moderate activity, while green means good to excellent activity.

Scheme 4

The general synthetic route for the alkylidene-hydrazinyl-thiazole derivatives.

Figure 10

Structures of the antimicrobial alkylidene-hydrazinyl-thiazole compounds.

Scheme 5

The general synthetic route for the alkylidene- and arylidene-hydrazinyl-thiazolin-4-one derivatives. Legend: abs.—absolute; anh.—anhydrous.

Figure 11

Structures of the antimicrobial 2-aryl-methylene-hydrazinyl-thiazolin-4-one derivatives.

Figure 12

The unfavorable attempt to replace the thiazole ring with a thiazolin-4-one ring supplementary substituted in the fifth position. (+) means activity against a strain. If the number of (+) increases, it means that the activity is better on certain strains. Similarly for the colors scheme (reffering to the heat bars): red means no or low activity, orange-yellow means low or moderate activity, while green means good to excellent activity.

Figure 13

The development of antimicrobial 5-arylidene-thiazolin-4-one derivatives as potential tryptophanyl-tRNA inhibitors.

Figure 14

Structure-activity relationships in the antimicrobial 5-arylidene-thiazolin-4-one derivatives. (+) means activity against a strain. If the number of (+) increases, it means that the activity is better on certain strains. Similarly for the colors scheme (reffering to the heat bars): red means no or low activity, orange-yellow means low or moderate activity, while green means good to excellent activity.

Scheme 6

The general synthetic pathways for the antimicrobial aryl- and hetaryl-thiazolidine-2,4-dione derivatives. Legend: t—temperature; DMF—dimethylformamide; rt—room temperature; EtOH—ethanol; MW—microwave; W—watts.

Figure 15

SAR studies on the antibacterial activity of the 3,5-disubstituted-thiazolidine-2,4-diones. The colors scheme (reffering to the heat bars): red means no or low activity, orange-yellow means low or moderate activity, while green means good to excellent activity.

Scheme 7

The synthetic pathway for the antimicrobial 3,5-disubstituted thiazolidinediones containing a PABA moiety [135]. Legend: rt—room temperature; MW—microwave; Et₃N—triethylamine; THF—tetrahydrofuran; DMF—dimethylformamide; W—watts; t—temperature.

Figure 16

SAR studies in the antifungal N-substituted-5-hydroxyarylidene-thiazolidine-2,4-diones [139,140].

Scheme 8

The general synthetic route for the piperazin-4-yl-(acetyl-thiazolidine-2,4-dione) norfloxacin analogues [141]. Legend: Et₃N—triethylamine; THF—tetrahydrofuran; MW—microwave; W—watts; t—temperature.

Figure 17

SAR studies of the antifungal thiazolyl-1,2,4-triazole Schiff bases [148].

Figure 18

SAR studies of the antibacterial thiazolyl-1,2,4-triazole Schiff bases [149].

Scheme 10

The general synthetic route for the in-house thiazoles obtained through Hantzsch condensation [155,156,157,158,159,160,161,162,163].

Figure 19

Structures of the antimicrobial 1,4-phenylene-bisthiazoles [156,157,158].

Figure 20

SAR studies of antifungal 1,4-phenylene-bisthiazole acylhydrazone derivatives [158].

Figure 21

Structures of the antimicrobial 4-(5-salicylamide)-thiazole derivatives [155,159].

Figure 22

Structures of the antimicrobial 4,5′-bisthiazole derivatives [160].

Figure 23

The development process of the antifungal thymolyl-thiazoles (HF = hydrophobic fragment; HBA = hydrogen bond acceptor; HBD = hydrogen bond donor) [158,161,162].

Scheme 11

The general synthetic route and the structures of the antifungal thymolyl-thiazole derivatives [161,162]. Thymol was derivatized into two thioamide components (A5 and A6), which were then treated with variously substituted 2-bromoacetophenones to yield series 52–55. Legend: rt—room temperature; t—temperature; EtOH—ethanol.

Figure 24

Structures of the antifungal thymolyl-triazole derivatives [163]. Legend: MeOH—methanol; DMF—dimethylformamide; rt—room temperature.

Figure 25

Structures of the antibiofilm 2-(3,4,5-trimethoxyphenyl)-4-Ar-5-R-thiazoles [186].

Figure 26

Structures of the antibiofilm 1,4-phenylene-(2-phenyl)-bisthiazoles [187].

Figure 27

The structures of antibiofilm pyridyl-thiazolyl-oxadiazoline derivatives [188].

Scheme 12

The chemical synthesis route of the antibiofilm N-(oxazolylmethyl)-thiazolidinedione (64–67: a–d) [189]. Legend: DMSO—dimethyl sulfoxide; t—temperature; rt—room temperature.