The landscape of medicinal chemistry in drug discovery has witnessed significant transformations [1]. An era of drug discovery started with identification of β-lactam molecules as promising antibacterial agents [2]. This breakthrough led to the exploration of diverse molecular classes. Researchers and professionals in the field have modified crucial cores present in bioactive compounds to come up with novel potential drugs [3]. Despite these synthetic advancements, the undeniable prowess of nature remains unparalleled, evident in modern strategies of drug discovery that predominantly center around pharmacophoric hybridization, mimicking natural molecules, harnessing antimicrobial peptides, forming protein-drug conjugates, and leveraging cellular mechanisms, as exemplified by PROTAC degraders [4], [5], [6], [7], [8]. This shift in focus is notably influenced by the alarming and escalating situation of antimicrobial resistance [9]. The repercussions of this resistance are profound, manifesting in prolonged treatment durations, escalated costs, and a staggering number of fatalities each year [10].

β-Lactams have long been recognized as potent molecules in treating various bacterial infections [11]. Despite their continued prominence in therapeutics, a shift in prescription patterns has been observed from standalone β-lactams to combinations with β-.

lactamase inhibitors [12]. This alteration is driven by the emergence of antimicrobial resistance, wherein bacteria deploy β-lactamases as defense mechanisms, rendering β-lactam drugs ineffective [13]. The primary target of β-lactams is the penicillin binding protein (PBPs), crucial for inhibiting bacterial cell wall formation. However, the activity of β-lactams is compromised as they undergo hydrolysis by β-lactamases before engaging in this process, leading to diminished efficacy. To counteract this challenge, β-lactamase inhibitors are now co-prescribed alongside these antibiotics. Consequently, current efforts in β-lactam drug discovery are focused on developing both effective β-lactams and potent β-lactamase inhibitors, reflecting the evolving landscape of combating bacterial infections [14].

Indoles are found as important core in commercially available drugs to treat a range of diseases (Fig. 1 (I-III)) [15], [16]. They possess an array of bioactivities including antibacterial, antiviral, anti-inflammatory, antifungal, anticancer, antitubercular and antimalarial properties [17]. One important aspect of broad range of activities of indole derivatives is their inherent presence as a part of naturally occurring amino acid tryptophan. So, this allows indoles to be widely accepted in nature via various enzymes and receptor with very high binding affinities. Due to these high affinities the synthesized drug molecules can attain a favorable position in the binding pocket or active site of the target protein.

Chalcogens, including S and Se, are known to enhance the bioactivity of drug molecules, which may also be evident from their presence in commercially available drugs (Fig. 1 (II-VI, VIII)) [18], [19], [20]. Both S and Se are important parts of the amino acids, cysteine, methionine and selenocysteine ​​which address their presence in bioactive molecules. Recently, a term “magic chloro effect” coined by Ishihara research group to address the chloro substituent in medicinal chemistry [21]. This is evident by more than 250 chloro containing FDA approved drugs (Fig. 1 (VII-IX)) [22]. The primary theories explaining the crucial role of chlorine (Cl) in medicinal chemistry center on two key aspects. Firstly, chlorine enhances the electrophilic reactivity of the C-Cl carbon, enabling it to readily engage in reactions with bio-nucleophiles. Secondly, chlorine contributes to an increase in the lipophilicity of the entire molecule. This increased lipophilicity results in an elevated concentration of the drug at the target site, emphasizing its significance in pharmacological effectiveness.

Pharmacophoric hybridization is an important area of modern drug discovery [4]. It simply means the combination of two different pharmacophores with two different modes of action into one. Another important aspect of pharmacophoric hybrids is that one core of the hybridized drug can also be used to increase the affinity of the hybridized drug so that the other core can more precisely target cellular functions. Based on this approach many research groups have reported bioactive molecular hybrids of β-lactams with azoles, isatin, pyrrolidines, pyrrolizidines, anthraquinone, aziridines, azides and purines [23], [24], [25], [26], [27], [28], [29], [30]. Our group has been also actively engaged in the design and synthesis of pharmacophoric hybrids of β-lactams with target antimicrobial activities. In this regard recently we have successfully developed thiophene-β-lactam hybrids X and 3-aroyl-thiourea/urea-β-lactam XI hybrids to possess antimicrobial properties (Fig. 2) [31], [32]. The biological assay revealed excellent antimicrobial activities of some target derivatives with respect to references. To gain much insights into the binding pattern molecular docking studies were carried out.

The need for new bioactive derivatives, molecular diversity, understanding of ligand receptor interactions, the above biological activity of indoles and β-lactams, and beneficial effects of chalcogens and chloros led us to club these parts into single pharmacophoric entities (Fig. 3). More precisely we envisage introducing indole at the C-4 position of the β-lactam ring and want to investigate the effect of chalcogen and chloro on the antimicrobial properties of the synthesized hybrid. The reaction methodology was developed based on our previous research findings [31], [32]. For better understanding of biological data molecular docking simulation were carried out to gain insights into the ligand receptor complex.